Methods and apparatuses for remodeling tissue of or adjacent to a body passage

ABSTRACT

Medical devices and methods for making and using the same are disclosed. An example method may include renal-denervation treatment method. The method may include delivering an RF energy treatment to a tissue proximate a renal artery using a catheter assembly of a renal denervation catheter system. The denervation system may include an RF energy generator coupled with the catheter assembly by a controller. The method may also include applying neural activity stimulation to the tissue proximate the renal artery using the catheter assembly, assessing stimulated neural activity response of the tissue using the catheter assembly, and determining a parameter of the RF energy treatment based on the assessed neural activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 to U.S.Provisional Application Ser. No. 61/580,141 filed Dec. 23, 2011, U.S.Provisional Application Ser. No. 61/632,624 filed Jan. 27, 2012, U.S.Provisional Application Ser. No. 61/633,154 filed Feb. 6, 2012, U.S.Provisional Application Ser. No. 61/743,238 filed Aug. 29, 2012, U.S.Provisional Application Ser. No. 61/743,225 filed Aug. 29, 2012, andU.S. Provisional Application Ser. No. 61/743,237 filed Aug. 29, 2012,the entire disclosures of which are herein incorporated by reference.

BACKGROUND

A wide variety of intracorporeal medical devices have been developed formedical use, for example, intravascular use. Some of these devicesinclude guidewires, catheters, and the like. These devices aremanufactured by any one of a variety of different manufacturing methodsand may be used according to any one of a variety of methods. Of theknown medical devices and methods, each has certain advantages anddisadvantages. There is an ongoing need to provide alternative medicaldevices as well as alternative methods for manufacturing and usingmedical devices.

BRIEF SUMMARY

This disclosure provides design, material, manufacturing method, and usealternatives for medical devices. An example method may include a methodfor treating a patient having high blood pressure. The method mayinclude providing a device. The device may include a catheter extendingalong a longitudinal axis. A balloon having an unexpanded state and anexpanded state may be coupled to an end of the catheter. The balloon mayhave a plurality of cylindrical treatment zones extending along thelongitudinal axis in the expanded state. A plurality of electrode padassemblies may be mounted to the balloon. Each electrode pad assemblymay include a substrate supporting first and second electrode pads witheach electrode pad having a pair of elongate bipolar electrodes. Theelectrode pads of each electrode pad assembly may be longitudinally andcircumferentially offset from one another. The method may also includeexpanding the balloon in the renal artery so as to electrically couplethe electrodes with a wall of the renal artery and driving bipolarenergy between the electrodes of each bipolar pair so as totherapeutically alter nerves surrounding the renal artery such that thehigh blood pressure of the patient is mitigated.

Each electrode pad may include a temperature sensor disposed between theelectrodes of the pair. The expanding of the balloon thermally maycouple the temperature sensors with the wall of the renal artery. Insome embodiments, the method may further include directing the energy tothe bipolar pairs in response to a temperature signal from thetemperature sensor so as to heat the wall approximately evenly.

The electrode pad assemblies may be arranged on the balloon so that atleast some of the electrode pads are longitudinally separated from acircumferentially adjacent electrode pad. In some embodiments, themethod may further include advancing the balloon into the renal arteryby flexing the balloon between the longitudinally separated electrodepads.

Another example method may include a method for treating a bodypassageway. The method may include providing a device. The device mayinclude a catheter extending along a longitudinal axis. A balloon havingan unexpanded state and an expanded state may be coupled to an end ofthe catheter. The balloon may have a plurality of cylindrical treatmentzones extending along the longitudinal axis in the expanded state. Aplurality of electrode assemblies may be coupled to the balloon. Eachelectrode assembly may include a distal electrode pad and a proximalelectrode pad. The distal electrode pad may be longitudinally separatedfrom the proximal electrode pad by an intermediate tail. Each electrodepad may include a bipolar electrode pair. The distal electrode pad andproximal electrode pad may be circumferentially offset from one anotherin the expanded state of the balloon. The plurality of electrode padsmay be each longitudinally arranged such that each cylindrical treatmentzone includes at least one of the distal and proximal electrode pads ofat least one of the plurality of electrode pad assemblies. Theintermediate tail of each electrode assembly may extend in thelongitudinal direction such that the distal electrode pad and proximalelectrode pad of any particular electrode pad assembly occupynon-adjacent treatment zones on the balloon. The method may also includeexpanding the balloon in a section of a body passageway. The section maybe elongated along an axis. The method may also include activating theelectrode pads while the balloon is expanded to deliver energy to thesection of body passageway, such that the section of body passagewayreceives a plurality of non-contiguous treatments along the longitudinalaxis.

Activating the electrode pads may create at least one lesion on thesection of body passageway for each treatment zone of the balloon. Thelesions may not contact one another. For example, the at least onelesion of each treatment zone may not axially overlap the at least onelesion of an adjacent treatment zone.

The method may include monitoring temperature at each of the electrodeassemblies. Monitoring temperature may include using at least one of theelectrode assemblies to monitor temperature of one of its bipolarelectrode pairs using a heat sensing device and/or monitoringtemperature may include using at least one of the electrode assembliesto monitor temperature of one of its bipolar electrode pairs using aheat sensing device of the other bipolar electrode pair.

Each bipolar electrode pair may include a plurality of ground electrodesand a plurality of active electrodes. Each plurality of ground andactive electrodes may be elongated along the axis and/or each pluralityof ground and active electrodes may be elongated transverse to the axis.

The balloon may have four cylindrical treatment zones. Two electrodeassemblies may be coupled to the balloon such that each zone includesone distal electrode pad or one proximal electrode pad. In someembodiments, three electrode assemblies may be coupled to the balloonsuch that each of two non-adjacent cylindrical treatment zones includestwo distal electrode pads or two proximal electrode pads and each of theother two non-adjacent cylindrical treatment zones includes one distalelectrode pad or one proximal electrode pad. In some embodiments, oneparticular cylindrical treatment zone may include one proximal electrodepad of one electrode assembly and two intermediate tails of the twoother electrode assemblies. In some embodiments, one particularcylindrical treatment zone may include two distal electrode pads of twodifferent electrode assemblies and one intermediate tail of theremaining electrode assembly.

The balloon may have four cylindrical treatment zones, and fourelectrode assemblies may be coupled to the balloon such that each of twonon-adjacent cylindrical treatment zones includes two distal electrodepads or two proximal electrode pads and each of the other twonon-adjacent cylindrical treatment zones includes one distal electrodepad or one proximal electrode pad. Two distal electrode pads of twodifferent electrode assemblies may occupy a particular cylindricaltreatment zone, with each of these two distal electrode pads beingcircumferentially separated by an intermediate tail of one of the othertwo other electrode assemblies. Two proximal electrode pads of twodifferent electrode assemblies may occupy a particular cylindricaltreatment zone, with each of these two proximal electrode pads beingcircumferentially separated by an intermediate tail of one of the othertwo other electrode assemblies.

An example device may include a catheter extending along a longitudinalaxis. A balloon may be coupled to an end of the catheter. A plurality ofelectrode assemblies may be mounted to the balloon. Each electrodeassembly may comprise first and second longitudinally separatedelectrode pads. The electrode pads of each electrode assembly may becircumferentially offset from one another in the expanded state of theballoon. The plurality of electrode assemblies may be longitudinallyarranged such that one of the electrode pads of one of the plurality ofelectrode assemblies is disposed longitudinally between the electrodepads of another of the electrode assemblies.

Another example device may include a catheter extending along alongitudinal axis. A balloon may be coupled to an end of the catheter.The balloon may have a plurality of cylindrical treatment zonesextending along the longitudinal axis in an expanded state. A pluralityof electrode assemblies may be to the balloon. Each electrode assemblymay include a distal electrode pad and a proximal electrode pad. Thedistal electrode pad may be longitudinally separated from the proximalelectrode pad by an intermediate tail. Each electrode assembly mayinclude a bipolar electrode pair. The distal electrode pad and proximalelectrode pad may be circumferentially offset from one another in theexpanded state of the balloon. The plurality of electrode pads may beeach longitudinally arranged such that each cylindrical treatment zoneincludes at least one of the distal and proximal electrode pads of atleast one of the plurality of electrode assemblies. The intermediatetail of each electrode assembly may extend in the longitudinal directionsuch that the distal electrode pad and proximal electrode pad of anyparticular electrode assembly occupy non-adjacent treatment zones on theballoon.

The balloon may have four cylindrical treatment zones, and two electrodeassemblies may be coupled to the balloon such that each zone includesone distal electrode pad or one proximal electrode pad.

The balloon has four cylindrical treatment zones, and three electrodeassemblies may be coupled to the balloon such that each of twonon-adjacent cylindrical treatment zones includes two distal electrodepads or two proximal electrode pads and each of the other twonon-adjacent cylindrical treatment zones includes one distal electrodepad or one proximal electrode pad.

One particular cylindrical treatment zone may include one proximalelectrode pad of one electrode assembly and two intermediate tails ofthe two other electrode assemblies.

One particular cylindrical treatment zone may include two distalelectrode pads of two different electrode assemblies and oneintermediate tail of the remaining electrode assembly.

The balloon may have four cylindrical treatment zones, and fourelectrode assemblies may be coupled to the balloon such that each of twonon-adjacent cylindrical treatment zones includes two distal electrodepads or two proximal electrode pads and each of the other twonon-adjacent cylindrical treatment zones includes one distal electrodepad or one proximal electrode pad.

Two distal electrode pads of two different electrode assemblies mayoccupy a particular cylindrical treatment zone, with each of these twoproximal electrode pads being circumferentially separated by anintermediate tail of one of the other two other electrode assemblies.

Two proximal electrode pads of two different electrode assemblies mayoccupy a particular cylindrical treatment zone, with each of these twoproximal electrode pads being circumferentially separated by anintermediate tail of one of the other two other electrode assemblies.

Each electrode pad may include a ground electrode and an activeelectrode.

Each electrode pad may include a heat sensing device.

Each electrode assembly may further comprises a proximal tail extendingfrom the proximal electrode pad.

For each electrode assembly, the intermediate tail comprises anintermediate ground line, intermediate active electrode line, andintermediate heat sensor line, and the proximal tail comprises theintermediate active electrode line, intermediate heat sensor line, aproximal ground line, proximal active electrode line, and proximal heatsensing line.

The width of the proximal tail may be approximately 150% of the width ofthe intermediate tail.

The intermediate ground line may be extended on an axis shared with theproximal ground line.

A distal ground electrode of the distal electrode pad and a proximalground electrode of the proximal electrode pad may both extend along theaxis shared with the intermediate and proximal ground lines, such thatthe distal ground electrode, intermediate ground line, proximal groundelectrode, and proximal ground line all extend along on the axis.

Another example device may include an expandable balloon including anouter surface and a plurality of discrete flexible circuits extendingalong the outer surface of the expandable balloon. At least some of theflexible circuits each may include two or more energy treatment sites.At least some portions of some of the flexible circuits may be shaped toat least approximately key to a shape of at least one adjacent flexiblecircuit.

At least some of the flexible circuits may each include a distalelectrode pad, a proximal electrode pad, an intermediate tail extendingbetween the distal and proximal electrode pads, and a proximal tailextending proximally away from the proximal electrode pad.

At least some of the distal electrode pads may be positioned proximateadjacent intermediate tails and wherein at least some of the proximalelectrode pads may be positioned proximate adjacent intermediate tails.

At least some portions of some of the flexible circuits may be shaped tonot key to a shape of at least one adjacent flexible circuit.

The energy treatment sites of at least some of the flexible circuits maybe longitudinally and circumferentially offset relative to one another.

The energy treatment sites may each comprise a pair of adjacent bipolarelectrodes.

The energy treatment sites may each further comprise a temperaturesensor positioned between the pair of adjacent bipolar electrodes.

Another example device may include an elongated catheter, an expandableballoon associated with the catheter, and a plurality ofcircumferentially spaced flexible circuits extending longitudinallyalong a surface of the expandable balloon. Each flexible circuit mayinclude at least one electrode. The electrodes may be spaced apartaxially and circumferentially relative to each other. The flexiblecircuits may be adhesively secured to the expandable balloon and includea plurality of openings extending through the flexible circuits. Theopenings may be configured to increase flexibility of the flexiblecircuits.

The electrodes may be monopolar electrodes.

Each flexible circuit may include a first monopolar electrode and asecond monopolar electrode. The first and second monopolar electrodesmay be circumferentially offset. The monopolar electrodes of a firstflexible circuit may be longitudinally offset relative to the monopolarelectrodes of adjacent flexible circuits.

The device may further comprises a common electrode. The commonelectrode may be positioned on the surface of the expandable balloon.

At least some corners of the flexible circuits may be rounded corners.

Each flexible circuit may include at least one conductor trace extendinglongitudinally along the flexible circuit.

Each flexible circuit may include at least two discrete conductor tracesextending longitudinally along the flexible circuit.

Another example device may include an expandable balloon including anouter surface. A plurality of discrete flexible circuits may extendalong the outer surface of the expandable balloon. At least some of theflexible circuits may each include two or more monopolar electrodes. Atleast some portions of some of the flexible circuits may be shaped to atleast approximately key to a shape of at least one adjacent flexiblecircuit.

The flexible circuits may be adhesively bonded to the outer surface ofthe balloon. The flexible circuits may include openings configured toincrease the flexibility of the circuits.

Another example device may include an expandable balloon including anouter surface. At least one flexible circuit may be mounted on the outersurface of the expandable balloon. The at least one flexible circuit mayinclude a first insulating layer.

At least one heat sensing device may be positioned at least partiallywithin the first insulating layer. A conductive layer may be disposedabove the first insulating layer, at least a portion of which may beelectrically coupled to the heat sensing device. A second insulatinglayer may be disposed above the conductive layer. At least one monopolarelectrode may be associated with the conductive layer.

The at least one electrode may be positioned above the second insulatinglayer and may be coupled to the conductive layer through the secondinsulating layer.

The heat sensing device may have a thickness of less than approximately0.15 mm.

The at least one monopolar electrode may include at least two monopolarelectrode pads, and wherein the heat sensing device may be positionedbetween the pair of monopolar electrode pads.

The heat sensing device may be positioned relative to the monopolarelectrode such that the heat sensing device is configured to measure atemperature representative of both the monopolar electrode and a tissuewhen the device is in contact with the tissue.

The heat sensing device may or may not be electrically coupled to themonopolar electrode.

The device may be configured to be fully inflated at an inflationpressure of 10 atmospheres or less or at an inflation pressure of 6atmospheres or less.

Another example device may include an expandable, non-compliant balloonincluding an outer surface. The expandable balloon may be configured tobe fully inflated at an inflation pressure of 10 atmospheres or less. Aplurality of thin film flexible circuits may extend longitudinally alongan outer surface of the balloon. At least one of the flexible circuitsmay include a first insulating layer facing the outer surface of theballoon, at least one heat sensing device, a conductive layer above thefirst insulating layer, a second insulating layer above the conductivelayer, and at least one electrode associated with the conductive layer.The maximum thickness of the flexible circuit may be less than 0.2 mm.

The maximum thickness of the flexible circuit may be equal to the sum ofthicknesses of the first insulating layer, the heat sensing device, theconductive layer, the second insulating layer, and the electrode.

The at least one electrode may be a monopolar electrode.

The heat sensing device may be positioned at least partially within thefirst insulating layer.

The thickness of the heat sensing device may be less than 0.15 mm.

The balloon may be configured to be fully inflated at an inflationpressure of 6 atmospheres or less.

An example electrode pad may include a base insulating layer having abase opening. A heat sensing component may be positioned within the baseopening and may have a first pole and a second pole. A conductive layermay be on top of the base insulating layer. The conductive layer mayinclude a first trace connected to the first pole, a second traceconnected to the second pole, and a third trace. A top insulating layermay be layered on top of the conductive layer. The top insulating layermay have a first plurality of openings over the first trace and a secondplurality of openings over the second trace. A first plurality ofelectrodes may be layered on top of the top insulating layer and may beconductively coupled to the first trace via the first plurality ofopenings in the top insulating layer. A second plurality of electrodesmay be layered on top of top insulating layer and may be conductivelycoupled to the second trace via the second plurality of openings.

The base insulating layer may have a rectangular shape extending inlateral and longitudinal directions. The rectangular shape maytransition to a narrow extension extending in the longitudinaldirection.

The first trace may comprise a first elongate electrode trace extendingin the longitudinal direction.

The first trace may further comprise a first ground pad laterallydisplaced from the first elongate trace. The ground pad may beelectronically coupled to the heat sensing component.

The third trace may comprise a power pad coupled to the heat sensingcomponent.

Distal portions of each of the first elongate electrode trace and groundpad may be connected by a bridge portion.

Each of first plurality of electrodes may be elongated in thelongitudinal direction.

The second trace may comprise a second elongate electrode traceextending in the longitudinal direction.

The second elongate electrode trace may be substantially parallel to thefirst elongate electrode trace.

The base insulating layer and top insulating layer may each comprise aflexible polymer. The flexible polymer may comprise polyimide. Thepolyimide may be approximately 0.0013 mm thick.

The top insulating layer may be discretely shaped with respect to anupper surface of the conductive layer.

The top insulating layer may substantially match the bottom insulatinglayer in shape.

The heat sensing component may comprise a thermistor. The thermistor maybe approximately 0.10 mm thick.

The surface area of the first plurality of electrodes may besubstantially equal to the surface area of the second plurality ofelectrodes.

The first and second plurality of electrodes may comprise gold.

An example electrode assembly may include a base insulating layercomprising a distal electrode pad, an intermediate tail, a proximateelectrode pad. The base insulating layer may have a thermistor opening.The base layer may be rectangular and extending in longitudinal andlateral directions. A thermistor may be positioned within the thermistoropening and may have a ground pole and a power pole. A conductive layermay be layered on top of the base insulating layer. The conductive layermay include a ground trace connected to the first pole, a second traceconnected to the second pole, and a third trace. A top insulating layermay be layered on top of the conductive layer. The top insulating layermay have a first plurality of openings over the first trace and a secondplurality of openings over the second trace. A first plurality ofelectrodes may be layered on top of the top insulating layer and may beconductively coupled to the first trace via the first plurality ofopenings in the top insulating layer. A second plurality of electrodesmay be layered on top of the top insulating layer and may beconductively coupled to the second trace via the second plurality ofopenings.

An example flexible circuit assembly may include a distal electrode pad.The distal electrode pad may include a distal base insulating layerhaving a distal thermistor opening, a distal thermistor being positionedwithin the distal thermistor opening and having a first distal pole anda second distal pole, a distal conductive layer layered on top of thedistal base insulating layer, the distal conductive layer comprising adistal ground trace linearly extending along a ground axis and coupledto the first distal sensor pole, a distal sensor trace coupled to thesecond distal pole, and a distal active electrode trace, a distal topinsulating layer layered on top of the distal conductive layer, thedistal top insulating layer having a first distal plurality of openingsover the first distal trace and a second distal plurality of openingsover the second distal trace, a first distal plurality of electrodesextending along the ground axis and layered on top of the distal topinsulating layer and being conductively coupled to the distal groundtrace via the first distal plurality of openings in the distal topinsulating layer, and a second distal plurality of electrodes layered ontop of the distal top insulating layer, and laterally displaced from thefirst distal plurality of electrodes on a first lateral side of theground axis, and being conductively coupled to the distal activeelectrode trace via the second distal plurality of openings. Anintermediate tail may proximally extend from the distal electrode pad.The intermediate tail may include an intermediate base insulating layerextending from the distal base insulating layer and an intermediateconductive layer layered on top of the intermediate insulating layer.The intermediate conductive layer may include an intermediate groundline extending from the distal ground trace along the ground axis, anintermediate active electrode line coupled to the distal activeelectrode trace and extending along a first outer axis parallel to theground axis on the first lateral side of the ground axis, and anintermediate sensor line coupled to the distal sensor trace andextending along a first inner axis parallel to the ground axis on thefirst lateral side of the ground axis and between the ground axis andfirst outer axis. An intermediate top insulating layer may be layered ontop of the intermediate conductive layer. A proximal electrode pad maybe coupled to the intermediate extension member. The proximal electrodepad may include a proximal base insulating layer having a proximalthermistor opening, a proximal thermistor being positioned within theproximal thermistor opening and having a first proximal pole and asecond proximal pole, and a proximal conductive layer layered on top ofthe distal base insulating layer. The proximal conductive layer mayinclude a proximal ground trace linearly extending along the ground axisand coupled to the first proximal sensor pole, a distal sensor tracecoupled to the second distal pole, and a proximal active electrodetrace. A proximal top insulating layer may be layered on top of theproximal conductive layer. The proximal top insulating layer may have afirst proximal plurality of openings over the first proximal distaltrace and a second proximal plurality of openings over the secondproximal trace. A proximal distal plurality of electrodes may extendalong the ground axis and layered on top of the proximal top insulatinglayer and being conductively coupled to the proximal ground trace viathe first proximal plurality of openings in the proximal top insulatinglayer. A second proximal plurality of electrodes may be layered on topof the proximal top insulating layer, and laterally displaced from thefirst proximal plurality of electrodes on a second lateral side of theground axis, and being conductively coupled to the proximal activeelectrode trace via the second proximal plurality of openings. Aproximal tail may proximally extend from the proximal electrode pad. Theproximal tail may include a proximal insulating layer extending from theproximal base insulating layer and a proximal conductive layer layeredon top of the proximal insulating layer. The proximal conductive layermay include a proximal ground line extending from the proximal groundtrace along the ground axis, a proximal active electrode line coupled tothe distal active electrode trace and extending along a second outeraxis parallel to the ground axis on the second lateral side of theground axis, a proximal sensor line coupled to the proximal sensor traceand extending along a second inner axis parallel to the ground axis onthe second lateral side of the ground axis and between the ground axisand second outer axis, an intermediate active electrode line, and anintermediate sensor line. A proximal top insulating layer may be layeredon top of the proximal conductive layer.

Another example device may include an expandable balloon including anouter surface and at least one flexible circuit mounted on the outersurface of the expandable balloon. The at least one flexible circuit mayinclude a first insulating layer, at least one heat sensing devicepositioned at least partially within the first insulating layer, aconductive layer above the first insulating layer, at least a portion ofwhich is electrically coupled to the heat sensing device, a secondinsulating layer above the conductive layer, and at least one electrodeassociated with the conductive layer.

The at least one electrode may be positioned above the second insulatinglayer and may be coupled to the conductive layer through the secondinsulating layer.

The heat sensing device may have a thickness of less than approximately0.15 mm. For example, the heat sensing device may have a thickness ofapproximately 0.1 mm.

The at least one electrode may be a pair of bipolar electrodes.

The heat sensing device may be positioned between the pair of bipolarelectrodes.

The heat sensing device may be positioned relative to the pair ofbipolar electrodes such that the heat sensing device is configured tomeasure a temperature representative of both the bipolar electrodes anda tissue when the device is in contact with the tissue.

The heat sensing device may be electrically coupled to one of the pairof bipolar electrodes.

The pair of bipolar electrodes may include a plurality of activeelectrodes and a plurality of ground electrodes.

The plurality of active electrodes may be arranged along a firstlongitudinal axis and the plurality of ground electrodes are arrangedalong a second longitudinal axis that is offset from and approximatelyparallel to the first longitudinal axis.

The heat sensing device may be positioned relative to the at least oneelectrode such that the heat sensing device may be configured to measurea temperature representative of both the at least one electrode and atissue when the device is in contact with the tissue.

Another example method may include a method for treating a patienthaving high blood pressure. The method may include providing a device.The device may include a catheter, an expandable balloon coupled to thecatheter and including an outer surface, and at least one flexiblecircuit mounted on the outer surface of the expandable balloon. The atleast one flexible circuit may include a first insulating layer, atleast one heat sensing device positioned at least partially within thefirst insulating layer, a conductive layer above the first insulatinglayer, at least a portion of which is electrically coupled to the heatsensing device, a second insulating layer above the conductive layer,and at least one electrode associated with the conductive layer. Themethod may also include expanding the balloon in a renal artery of thepatient and driving energy through the at least one electrode so as totherapeutically alter at least one nerve proximate the renal artery suchthat the high blood pressure of the patient is mitigated.

Providing the device may include providing the device with at least apair of bipolar electrodes and the heat sensing device positionedbetween the pair of bipolar electrodes.

The method may also include using the heat sensing device to measure atemperature representative of both the at least one electrode and of awall of the renal artery.

Another example device may include a catheter, an expandable ballooncoupled to the catheter and including an outer surface, and at least oneflexible circuit mounted on the outer surface of the expandable balloon.The at least one flexible circuit may include a first insulating layer,at least one heat sensing device positioned at least partially withinthe first insulating layer, a conductive layer above the firstinsulating layer, at least a portion of which is electrically coupled tothe heat sensing device, a second insulating layer above the conductivelayer, and at least one electrode associated with the conductive layer.

An example catheter may include an elongate flexible catheter body. Anexpandable structure may be associated with the catheter body and mayinclude a radially expandable balloon and a plurality of flexiblecircuits extending along an outer surface of the balloon, each flexiblecircuit including at least one electrode and at least one temperaturesensor. The expandable structure may have an outer diameter of less than4 mm when in an expanded configuration.

The outer diameter of the expandable structure may be betweenapproximately 1 mm and 3 mm.

The balloon may be non-cannulated.

At least a portion of the outer surface of the balloon may be a flexiblepolyimide film. The flexible polyimide film may define a base insulativelayer of the plurality of flexible circuits.

An upper surface of the base insulative layer of the balloon maydirectly contact a conductive layer of at least one of the flexiblecircuits.

Each flexible circuit may include a base insulative layer adjacent theouter surface of the balloon.

An example system for renal denervation of a patient having a primaryrenal artery extending between an aorta and a kidney and an accessoryrenal artery extending between the aorta and the kidney may include afirst balloon catheter and a second balloon catheter, each having aballoon with a small profile configuration and a large profileconfiguration, with a plurality of flexible circuits extending along anouter surface of each balloon, each flexible circuit including at leastone electrode. At least one of the balloons may have a large profileconfiguration that is less than 4 mm in outer diameter. A power sourcemay be electrically coupled to the electrodes of the first and secondballoon catheters and may be configured to energize the electrodes witha renal denervation energy.

One of the balloons may have a large profile configuration that is equalto or greater than 4 mm in outer diameter.

The first and second balloons may have large profile configurations thatare different outer diameter sizes.

The system may be used for renal denervation of a patient further havinga second renal artery extending between the aorta and a second kidney.The system may further comprising a third balloon catheter having asmall profile configuration and a large profile configuration, with aplurality of flexible circuits extending along an outer surface of thethird balloon, each flexible circuit including at least one electrode;and wherein the electrodes of the third balloon catheter areelectrically coupled to the power source.

The first, second and third balloons, when in the large profileconfigurations, may define different outer diameters from one another.The outer diameter of the third balloon when in the large profileconfiguration may be greater than or equal to 4 mm.

An example renal denervation method may include positioning a radiallyexpandable structure of an elongate flexible catheter body at a locationin an accessory renal artery connecting an aorta to a kidney, the aortaand the kidney further connected by a primary renal artery, the radiallyexpandable structure comprising a plurality of electrodes, expanding theradially expandable structure such that at least a subset of theelectrodes engage a wall of the accessory renal artery, and using apower source electrically coupled to the electrodes, energizing at leasta subset of the plurality of electrodes to deliver energy to tissueproximate the accessory renal artery.

The method may also include positioning the radially expandablestructure at a location in the primary renal artery, expanding theradially structure such that at least some of the electrodes engage awall of the primary renal artery, and energizing at least some of theelectrodes to deliver energy to tissue proximate the primary renalartery.

The method may also include positioning a second radially expandablestructure of a second elongate flexible catheter body at a location inthe primary renal artery, expanding the second radially expandablestructure such that at least a subset of a plurality of electrodes ofthe second radially expandable structure engage a wall of the primaryrenal artery, and energizing at least a subset of the electrodes of thesecond radially expandable structure to deliver energy to tissueproximate the primary renal artery.

Energizing the electrodes may include a plurality of energizationcycles. The electrodes in the subset of energized electrodes may varybetween at least some of the energization cycles. An energy outputsetting of the power source may vary between at least some of theenergization cycles.

Another example renal denervation method may include positioning aradially expandable structure of an elongate flexible catheter body in arenal artery connecting an aorta to a kidney. The radially expandablestructure may comprise a plurality of electrodes. The method may alsoinclude expanding the radially expandable structure such that a subsetof the electrodes engage a wall of the renal artery. Another subset ofthe electrodes may be in the aorta. The method may also include using apower source electrically coupled to the electrodes, energizing at leastsome of the subset of the electrodes engaged with the wall of the renalartery.

Another example renal denervation method may include positioning aradially expandable structure of an elongate flexible catheter body in arenal artery connecting an aorta to a kidney. The radially expandablestructure may comprise a plurality of electrodes. The method may alsoinclude expanding the radially expandable structure such that at least asubset of the electrodes engage a wall of the renal artery, using apower source electrically coupled to the electrodes, energizing at leastsome of the subset of the electrodes engaged with the wall of the renalartery, re-positioning the radially expandable structure to a secondposition in the renal artery, at the second position, expanding theradially expandable structure such that a subset of the electrodesengage a wall of the renal artery and a different subset of theelectrodes are in the aorta, and at the second position, energizing atleast some of the subset of the electrodes engaged with the wall of therenal artery.

The renal artery may comprise an accessory renal artery. A primary renalartery may also connects the aorta to the kidney.

An example system for renal denervation of a patient may have a primaryrenal artery extending between an aorta and a kidney and an accessoryrenal artery extending between the aorta and the kidney may include afirst balloon catheter and a second balloon catheter, each having aballoon with a small profile configuration and a large profileconfiguration, with a plurality of flexible circuits extending along anouter surface of each balloon, each flexible circuit including at leastone electrode. At least one of the balloons may have a large profileconfiguration that is less than 4 mm in outer diameter. The system mayalso include a power source configured to electrically couple to theflexible circuits of the first and second balloon catheters andconfigured to energize at different times the electrodes of the firstand second balloon catheters with a renal denervation energy.

One of the balloons may have a large profile configuration that is equalto or greater than 4 mm in outer diameter.

The first and second balloons may have large profile configurations thatare different outer diameter sizes.

The system may be for renal denervation of a patient further having asecond renal artery extending between the aorta and a second kidney. Thesystem may further comprise a third balloon catheter having a smallprofile configuration and a large profile configuration, with aplurality of flexible circuits extending along an outer surface of thethird balloon, each flexible circuit including at least one electrode.The electrodes of the third balloon catheter may be configured forelectrically coupling to the power source.

The first, second and third balloons, when in the large profileconfigurations, may define different outer diameters from one another.

The outer diameter of the third balloon when in the large profileconfiguration may be greater than or equal to 4 mm.

An example catheter may include an elongate flexible catheter body. Anexpandable structure may be associated with the catheter body andincluding a radially expandable balloon and a plurality of flexiblecircuits extending along an outer surface of the balloon, each flexiblecircuit including at least one electrode and at least one temperaturesensor. The expandable structure may have an outer diameter of less than4 mm when in an expanded configuration.

The outer diameter of the expandable structure may be betweenapproximately 1 mm and 3 mm.

The balloon may be non-cannulated.

At least a portion of the outer surface of the balloon may be a flexiblepolyimide film.

The flexible polyimide film may define a base insulative layer of theplurality of flexible circuits.

An upper surface of the base insulative layer of the balloon maydirectly contact a conductive layer of at least one of the flexiblecircuits.

Each flexible circuit may include a base insulative layer adjacent theouter surface of the balloon.

An example system for renal denervation of a patient having a primaryrenal artery extending between an aorta and a kidney and an accessoryrenal artery extending between the aorta and the kidney is alsodisclosed. The system may include a first balloon catheter and a secondballoon catheter, each having a balloon with a small profileconfiguration and a large profile configuration, with a plurality offlexible circuits extending along an outer surface of each balloon, eachflexible circuit including at least one electrode, wherein at least oneof the balloons has a large profile configuration that is less than 4 mmin outer diameter. A power source may be electrically coupled to theelectrodes of the first and second balloon catheters and may beconfigured to energize the electrodes with a renal denervation energy.

One of the balloons may have a large profile configuration that is equalto or greater than 4 mm in outer diameter.

The first and second balloons may have large profile configurations thatare different outer diameter sizes.

The system may be for renal denervation of a patient further having asecond renal artery extending between the aorta and a second kidney. Thesystem may further comprise a third balloon catheter having a smallprofile configuration and a large profile configuration, with aplurality of flexible circuits extending along an outer surface of thethird balloon, each flexible circuit including at least one electrode;and wherein the electrodes of the third balloon catheter areelectrically coupled to the power source.

The first, second and third balloons, when in the large profileconfigurations, may define different outer diameters from one another.

The outer diameter of the third balloon when in the large profileconfiguration may be greater than or equal to 4 mm.

An example renal denervation method may include positioning a radiallyexpandable structure of an elongate flexible catheter body at a locationin an accessory renal artery connecting an aorta to a kidney, the aortaand the kidney further connected by a primary renal artery. The radiallyexpandable structure may comprise a plurality of electrodes. The methodmay further include expanding the radially expandable structure suchthat at least a subset of the electrodes engage a wall of the accessoryrenal artery and using a power source electrically coupled to theelectrodes, energizing at least a subset of the plurality of electrodesto deliver energy to tissue proximate the accessory renal artery.

The method may also include positioning the radially expandablestructure at a location in the primary renal artery, expanding theradially structure such that at least some of the electrodes engage awall of the primary renal artery, and energizing at least some of theelectrodes to deliver energy to tissue proximate the primary renalartery.

The method may also positioning a second radially expandable structureof a second elongate flexible catheter body at a location in the primaryrenal artery; expanding the second radially expandable structure suchthat at least a subset of a plurality of electrodes of the secondradially expandable structure engage a wall of the primary renal artery;and energizing at least a subset of the electrodes of the secondradially expandable structure to deliver energy to tissue proximate theprimary renal artery.

Energizing the electrodes may include a plurality of energizationcycles. The electrodes in the subset of energized electrodes may varybetween at least some of the energization cycles.

An energy output setting of the power source may vary between at leastsome of the energization cycles.

Another example renal denervation method may include positioning aradially expandable structure of an elongate flexible catheter body in arenal artery connecting an aorta to a kidney. The radially expandablestructure may include a plurality of electrodes. The method may alsoinclude expanding the radially expandable structure such that a subsetof the electrodes engage a wall of the renal artery, wherein anothersubset of the electrodes are in the aorta, and using a power sourceelectrically coupled to the electrodes, energizing at least some of thesubset of the electrodes engaged with the wall of the renal artery.

Another example renal denervation method may include positioning aradially expandable structure of an elongate flexible catheter body in arenal artery connecting an aorta to a kidney. The radially expandablestructure may include a plurality of electrodes. The method may alsoinclude expanding the radially expandable structure such that at least asubset of the electrodes engage a wall of the renal artery, using apower source electrically coupled to the electrodes, energizing at leastsome of the subset of the electrodes engaged with the wall of the renalartery, re-positioning the radially expandable structure to a secondposition in the renal artery, at the second position, expanding theradially expandable structure such that a subset of the electrodesengage a wall of the renal artery and a different subset of theelectrodes are in the aorta, and at the second position, energizing atleast some of the subset of the electrodes engaged with the wall of therenal artery.

The renal artery may include an accessory renal artery. A primary renalartery may also connects the aorta to the kidney.

Another example system for renal denervation of a patient having aprimary renal artery extending between an aorta and a kidney and anaccessory renal artery extending between the aorta and the kidney isalso disclosed. The system may include a first balloon catheter and asecond balloon catheter, each having a balloon with a small profileconfiguration and a large profile configuration, with a plurality offlexible circuits extending along an outer surface of each balloon, eachflexible circuit including at least one electrode. At least one of theballoons may have a large profile configuration that is less than 4 mmin outer diameter. The system may also include a power source configuredto electrically couple to the flexible circuits of the first and secondballoon catheters and configured to energize at different times theelectrodes of the first and second balloon catheters with a renaldenervation energy.

One of the balloons may have a large profile configuration that is equalto or greater than 4 mm in outer diameter.

The first and second balloons may have large profile configurations thatare different outer diameter sizes.

The system may be for renal denervation of a patient further having asecond renal artery extending between the aorta and a second kidney. Thesystem may further include a third balloon catheter having a smallprofile configuration and a large profile configuration, with aplurality of flexible circuits extending along an outer surface of thethird balloon, each flexible circuit including at least one electrode.The electrodes of the third balloon catheter may be configured forelectrically coupling to the power source.

The first, second and third balloons, when in the large profileconfigurations, may define different outer diameters from one another.

The outer diameter of the third balloon when in the large profileconfiguration may be greater than or equal to 4 mm.

An example method for treating tissue near a body passageway using anapparatus including a catheter having a plurality of electrodes, aradio-frequency energy generator, and a controller coupling the energygenerator to the plurality of electrodes and configured to selectivelyenergize the electrodes is also disclosed. The method may include usingthe apparatus to subject the tissue near the body passageway to aplurality of energy treatment cycles. A treatment cycle may includedetermining desired voltages for at least a subset of the electrodes formaintaining a predetermined target temperature profile proximate thesubset of electrodes, setting an output voltage of the energy generatorto correspond to the desired voltage determined for one of theelectrodes, and energizing at least some of the electrodes at the outputvoltage to deliver energy to the body passageway. The electrode used toset the output voltage may change in subsequent treatment cycles in atleast some instances.

The treatment cycle may further comprise identifying a first electrode.The first electrode may be used to set the output voltage if thedetermined voltage requirement for the first electrode is greater thanzero.

The identification of the first electrode may cycle through theplurality of electrodes from treatment cycle to treatment cycle.

The treatment cycles may further comprise identifying at least oneelectrode that is leakage-inducingly proximate to the first electrode.The at least one electrode that is leakage-inducingly proximate to thefirst electrode may not be energized during the treatment cycle.

The plurality of electrodes may comprise a plurality of bipolarelectrodes, and wherein identifying the at least one electrode that isleakage-inducingly proximate to the first electrode may compriseidentifying at least one electrode having a negative pole that isleakage-inducingly proximate a positive pole of the first electrode.

Determining desired voltage for an electrode of the subset of electrodesmay be based on a previous output voltage applied to the electrode ofthe subset of electrodes.

Determining desired voltage for the electrode of the subset ofelectrodes may also be based on differences between a measuredtemperature proximate the electrode of the subset of electrodes and thetarget temperature.

Determining desired voltage for the electrode of the subset ofelectrodes may be based on a current temperature error as well as anaverage temperature error over time for the electrode of the subset ofelectrodes.

The desired voltage may equal:

V=K _(L) V _(L) +K _(P) T _(e) +K _(I)∫^(t) _(t-n sec) T _(e AVE)

wherein V is the desired voltage, V_(L) is the previously calculatedoutput voltage, T_(e) is a temperature error for the electrode of thesubset of electrodes, K_(L), K_(P) and K_(I) are constants, and n is atime value ranging from 0 to t seconds.

The desired voltage may equal:

V = 0.75  V_(L) + K_(p)T_(e) + K_(I)∫_(t − 1  sec )^(t)T_(e A V E)

wherein V is the desired voltage, V_(L) is the previously calculatedoutput voltage, T_(e) is a temperature error for the electrode of thesubset of electrodes, and K_(P) and K_(I) are constants.

An example method for treating a body passageway using an apparatuscomprising an energy delivery device having a plurality of discreteenergy delivery sites, an energy generator, and a controller couplingthe energy delivery sites to the energy generator and configured toselectively energize the plurality of energy delivery sites is alsodisclosed. The method may include using the apparatus to subject thebody passageway to a plurality of treatment cycles. At least some of thetreatment cycles may include determining a plurality of possible outputlevels for at least a subset of the energy delivery sites formaintaining a predetermined parameter of the treatment, setting anactual output level of the energy generator to correspond to thepossible output level determined for one of the energy delivery sites,and energizing at least some of the energy delivery sites at the actualoutput level to deliver energy to the body passageway. The energydelivery site may be used to set the actual output level changes fromtreatment cycle to treatment cycle in at least some instances.

Determining a plurality of possible output levels may includedetermining a plurality of possible energization times.

Determining a plurality of possible output levels may includedetermining a plurality of possible output voltages.

Energizing at least some of the energy delivery sites at the actualoutput level may include energizing at least some of the energy deliverysites associated with a possible output level that is equal to orgreater than the actual output level set during the treatment cycle.

Determining the possible output level for one of the energy deliverysites may be based on an output level applied at the energy deliverysite in an immediately preceding treatment cycle.

Determining the possible output level for one of the energy deliverysites may also be based on a characterization of an error between anactual condition proximate the energy delivery site and thepredetermined parameter.

At least some of the treatment cycles may further comprise identifyingfrom the plurality of energy delivery sites a first energy deliverysite.

The identification of the first energy delivery site may cycle throughthe plurality of energy delivery sites from treatment cycle to treatmentcycle.

The possible output level determined for the first energy delivery sitemay be used to set the actual output level if the possible output leveldetermined for the first energy delivery site is greater than zero.

At least some of the energy delivery sites proximate the first energydelivery site may not be energized during the treatment cycle.

An example method for inducing a desired therapeutic change in tissueusing an electrosurgical system is also disclosed. The method mayinclude electrically coupling a plurality of electrodes of the system toa plurality of zones of the tissue and heating the tissue with aplurality of heating cycles. Each heating cycle may have an associatedselected zone and may include determining a desired potential for theselected zone in response to a desired characteristic, determining a setof the electrodes appropriate for application of the desired potential,and energizing the selected set of the electrodes with the desiredpotential. The method may also include monitoring temperature signalsfrom the zones and simultaneously inducing the desired therapeuticchange in the tissue of the zones by swapping the selected zone amongthe zones, and by identifying the desired change and the set ofelectrodes in response to the temperature signals.

The tissue may be disposed near a body passageway. The plurality ofelectrodes may be coupled with the zones by expanding an expandable bodywithin the passageway. The electrodes may include bipolar electrodessupported by the expandable body. The desired potentials may include abipolar electrical potential.

An example system for treating tissue near a body passageway may includea catheter having a plurality of electrodes, a radio-frequency energygenerator, and a controller coupling the energy generator to theplurality of electrodes and configured to selectively energize theelectrodes during a plurality of energy treatment cycles. During atreatment cycle, the system may be configured to determine desiredvoltages for at least a subset of the electrodes for maintaining apredetermined target temperature proximate the subset of electrodes, setan output voltage of the energy generator to correspond to the desiredvoltage determined for one of the electrodes, and energize at least someof the electrodes at the output voltage to deliver energy proximate thebody passageway; and wherein the system is configured to vary theelectrode used to set the output voltage from treatment cycle totreatment cycle in at least some instances.

An example energy generation apparatus may include a radio-frequencyenergy generator and a controller. The controller may be configured tocouple the energy generator to a catheter having a plurality ofelectrodes. The controller may be configured to selectively energize theelectrodes during a plurality of energy treatment cycles, includingdetermining desired voltages for at least a subset of the electrodes formaintaining a predetermined target temperature proximate the subset ofelectrode, setting an output voltage of the energy generator tocorrespond to the desired voltage determined for one of the electrodes,and energizing at least some of the electrodes at the set output voltageto deliver energy to the body passageway. The controller may beconfigured to vary the electrode used to set the output voltage fromtreatment cycle to treatment cycle in at least some instances.

An example method for treating a body passageway using an apparatuscomprising an energy delivery device having a plurality of discreteenergy delivery sites, an energy generator, and a controller couplingthe energy delivery sites to the energy generator and configured toselectively energize the plurality of energy delivery sites is alsodisclosed. The method may include using the apparatus to subject thebody passageway to a plurality of treatment cycles. At least some of thetreatment cycles may include selecting one of the energy delivery sitesas a primary energy delivery site, identifying at least a subset of theenergy delivery sites that are not energy leakage-inducingly proximateto the primary energy delivery site, and energizing at least some of thesubset of energy delivery sites. The energy delivery site may beselected as the primary energy delivery site changes from treatmentcycle to treatment cycle in at least some instances.

An example method for treating tissue near a body passageway using anapparatus having a plurality of electrodes, an energy generator, and acontroller coupling the energy generator to the plurality of electrodesand configured to selectively energize the electrodes is also disclosed.The method may include using the apparatus to subject the tissue nearthe body passageway to a plurality of energy treatment cycles. Atreatment cycle may include determining desired power settings for atleast a subset of the electrodes for maintaining a predetermined targettemperature profile proximate the subset of electrodes, setting anactual power setting of the energy generator to correspond to thedesired power setting determined for one of the electrodes, andenergizing at least some of the electrodes at the actual power settingto deliver energy to the body passageway. The electrode may be used toset the actual power setting changes in subsequent treatment cycles inat least some instances.

An example method for delivering an energy-based treatment to a tissueproximate a blood vessel is also disclosed. The method may includepositioning, at a location in the blood vessel, a radially expandablestructure of an elongate flexible catheter body, a plurality ofelectrodes being positioned on the radially expandable structure;expanding the radially expandable structure such that at least a subsetof the electrodes engage a wall of the blood vessel so at to establish aplurality of electrical circuits, each electrical circuit including oneof the electrodes and a portion of the tissue within a treatment zone;energizing the plurality of circuits in a time sequence using a powersource; and controlling the delivery of energy using a processor coupledwith the power source, such controlling including verifying the presenceof the electrical circuit, selectively energizing electrodes during thesequence, and regulating one or more parameters of the electricalcircuits such that energy delivered to the treatment zone heats tissuetherein to a temperature in a target temperature range, thereby inducinga tissue remodeling response.

The electrodes may be selectively energized by identifying anappropriate group of the electrodes and simultaneously energizing thegroup of electrodes during the sequence, and by repeatedly cyclingthrough the sequence. The group may be determined in response to aplurality of temperature signals associated with the portions of tissuewithin the treatment zone so that the group changes with the cycles. Theelectrodes may comprise monopolar electrodes positioned on the balloonand included in a plurality of flex circuits, each flex circuitincluding at least one of the monopolar electrodes.

The plurality of flex circuits may further comprise a temperaturesensing structure in proximity to at least one of the monopolarelectrodes, the temperature sensing structure being electrically coupledto the processor so as to provide feedback.

The balloon may be inflated with an inflation pressure of about 5atmospheres or less.

An expanded diameter of the expandable structure may be about 2 mm toabout 10 mm. For example, an expanded diameter of the expandablestructure may be about 3 mm or less.

An example method for delivering an energy-based treatment to a tissueproximate a blood vessel is also disclosed. The method may includepositioning an expandable structure of an elongate catheter at alocation in the blood vessel, the expandable structure including aplurality of electrodes, at least some of which are longitudinallyspaced along the expandable structure, the plurality of electrodeselectrically coupled to a power source; expanding the expandablestructure such that at least some of the plurality of electrodes contacta tissue; using a processor coupled with the power source, verifyingwhich of the plurality of electrodes are in contact with the tissue;selectively energizing at least one of the electrodes that is in contactwith the tissue; and controlling the delivery of energy using theprocessor to regulate one or more parameters of the energy treatmentbased on monitoring feedback from electrical circuits associated with atleast some of the electrodes such that energy delivered to a treatmentzone heats the tissue therein.

Verifying whether one of the electrodes is in contact with the tissuemay comprise measuring a characteristic of an electrical circuitassociated with the electrode and determining whether the measuredcharacteristic meets a criteria.

Selectively energizing the at least one electrode may compriseenergizing electrodes that meet the criteria and not energizingelectrodes that do not meet the criteria.

Measuring the characteristic of the electrical circuit may comprisemeasuring a resistance associated with the electrical circuit.

Selectively energizing the at least one electrode may compriseenergizing only the electrodes associated with measured resistances thatare within a pre-determined range.

Positioning the expandable structure including the plurality ofelectrodes may comprise positioning an expandable structure including aplurality of monopolar electrodes.

Positioning the expandable structure comprises positioning an expandablestructure including the plurality of monopoloar electrodes and a commonelectrode.

Determining whether the measured characteristic meets the criteria maycomprise determining whether a measured characteristic associated with afirst monopolar electrode meets a first criteria and determining whethera measured characteristic associated with a second monopolar electrodemeets a second criteria. The first and second criteria may be different.

Determining whether the measured characteristic meets the criteria maycomprise determining whether a measured characteristic associated with afirst monopolar electrode and a measured characteristic associated witha second monopolar electrode meets a single criteria.

An example system for delivering an energy-based treatment to a tissueproximate a blood vessel is also disclosed. The system may include anelongate catheter including an expandable structure at or near a distalend of the catheter. The expandable structure may include a plurality ofelectrodes, at least some of which are longitudinally spaced apart alongthe expandable structure. The system may also include a power sourceelectrically coupled to the plurality of electrodes and a processorconfigured to verify whether at least some of the plurality ofelectrodes are in contact with the tissue by measuring a characteristicof an electrical circuit associated with the at least some of theplurality of electrodes and determining whether the measuredcharacteristic meets a criteria. The processor may be configured toenergize at least one of the plurality of electrodes if the at least oneof the plurality of electrodes is verified as in contact with thetissue. The processor may be configured to control the delivery ofenergy to regulate one or more parameters of the energy treatment basedon monitoring feedback from at least some of the electrical circuitssuch that energy delivered to a treatment zone heats the tissue thereinto a temperature of about 55° C. to about 75° C. while tissue collateralto the treatment zone is heated to less than about 45° C.

The plurality of electrodes of the expandable structure may be aplurality of monopolar electrodes.

The expandable structure may further comprise at least one commonelectrode.

The elongate catheter may further comprise at least one commonelectrode.

The system may further comprise at least one common electrode pad.

An example method for delivering an energy-based treatment to a tissueproximate a blood vessel is also disclosed. The method may include usingan elongate catheter, positioning an expandable structure of anenergy-based treatment system at a location in the blood vessel, theexpandable structure positioned at or near a distal end of the catheterand including a plurality of monopolar electrodes. The energy-basedtreatment system may further comprise a common electrode and a powersource, the power source electrically coupled to the plurality ofmonopolar electrodes. The method may also include expanding theexpandable structure such that at least some of the plurality ofelectrodes contact a tissue; using a processor, measuring acharacteristic of a plurality of electrical circuits, each electricalcircuit associated with one of the plurality of monopolar electrodes andthe common electrode; using the processor, identifying a subset of themonopolar electrodes for energization, the identified subset ofelectrodes having measured characteristics that are within a desiredrange; and simultaneously energizing the one or more of the monopoloarelectrodes identified for energization.

The common electrode may be associated with the expandable structure.

Another example method for delivering an energy-based treatment to atissue proximate a blood vessel may include positioning an expandablestructure of an elongate catheter at a location in the blood vessel, theexpandable structure positioned at or near a distal end of the catheterand including a plurality of monopolar electrodes, at least some ofwhich are longitudinally spaced along the expandable structure, theplurality of electrodes electrically coupled to a power source;expanding the expandable structure such that at least some of theplurality of electrodes contact a tissue; selectively energizing asubset of the plurality of electrodes; and controlling the delivery ofenergy using a processor to regulate one or more parameters of theenergy treatment based on monitoring feedback from electrical circuitsassociated with at least some of the electrodes such that energydelivered to a treatment zone heats the tissue therein to a temperaturein a desired range.

The method may also include, prior to selectively energizing the subsetof the plurality of electrodes, identifying, using a processor, thesubset of electrodes for energization.

Identifying the subset of electrodes may include measuring acharacteristic of an electrical circuit associated with each of theplurality of electrodes.

Identifying the subset of electrodes may further comprise comparing,using the processor, the measured characteristics to identify the subsetfor energization.

Identifying the subset for energization may comprise identifying a groupof the electrodes with substantially similar measured characteristics.

Identifying the subset of electrodes may further comprise determiningwhether the measured characteristic associated with each of theplurality of electrodes meets a predetermined requirement.

Determining whether the measured characteristic associated with each ofthe plurality of electrodes meets a predetermined requirement maycomprise determining whether the measured characteristic associated witheach of the plurality of electrodes comes within a pre-determined range.

Determining whether the measured characteristic associated with each ofthe plurality of electrodes comes within a pre-determined range maycomprise using the same pre-determined range for each of the electrodes.

Determining whether the measured characteristic associated with each ofthe plurality of electrodes comes within a pre-determined range maycomprise using a different pre-determined range for at least some of theelectrodes.

An example method for treating tissue near a body passageway using anapparatus including a catheter having a plurality of monopolarelectrodes, a radio-frequency energy generator, and a controllercoupling the energy generator to the monopolar electrodes and configuredto selectively energize the monopolar electrodes is also disclose. Themethod may include using the apparatus to subject the tissue near thebody passageway to a plurality of energy treatment cycles. A treatmentcycle may include determining desired voltages for at least a subset ofthe monopolar electrodes for determining a predetermined targettemperature profile proximate the subset of monopolar electrodes;setting an output voltage of the energy generator to correspond to thedesired voltage determined for one of the monopolar electrodes; andenergizing at least one of the monopolar electrodes at the outputvoltage to deliver energy to the body passageway. The monopolarelectrode may be used to set the output voltage changes in subsequenttreatment cycles in at least some instances.

The treatment cycle further may include identifying a first monopolarelectrode;

wherein the first monopolar electrode is used to set the output voltageif the determined voltage requirement for the first monopolar electrodeis greater than zero.

The identification of the first monopolar electrode may cycle throughthe plurality of monopolar electrodes from treatment cycle to treatmentcycle.

The treatment cycle may further comprise identifying at least onemonopolar electrode that is associated with an electrical circuitcharacteristic that is substantially different from an electricalcircuit characteristic associated with the first monopolar electrode.The at least one monopolar electrode associated with the substantiallydifferent electrical circuit characteristic may not be energized duringthe treatment cycle.

The electrical circuit characteristic utilized for the identificationmay be an impedance measurement.

An example method for treating a body passageway using an apparatuscomprising an energy delivery device having a plurality of discretemonopolar energy delivery sites, a common electrode, an energygenerator, and a controller coupling the monopolar energy delivery sitesto the energy generator and configured to selectively energize theplurality of monopolar energy delivery sites is also disclosed. Themethod may include using the apparatus to subject the body passageway toa plurality of treatment cycles. At least some of the treatment cyclesmay comprise determining a plurality of possible output levels for atleast a subset of the monopolar energy delivery sites for maintaining apredetermined parameter of the treatment; setting an actual output levelof the energy generator to correspond to the possible output leveldetermined for one of the monopolar energy delivery sites; andenergizing at least some of the monopolar energy delivery sites at theactual output level to deliver energy to the body passageway. Themonopolar energy delivery site used to set the actual output level maychange from treatment cycle to treatment cycle in at least someinstances.

An method for treating a patient having congestive heart failure is alsodisclosed. The method may include positioning an expandable balloon in arenal artery of the patient, the expandable balloon including aplurality of electrode assemblies, at least some of the electrodeassemblies each including at least two bipolar electrode pairs, the twobipolar electrode pairs being longitudinally and circumferentiallyoffset from one another; expanding the balloon in the renal artery suchthat at least some of the bipolar electrode pairs are electricallycoupled to a wall of the renal artery; and energizing at least some ofthe bipolar electrode pairs so as to therapeutically alter at least onenerve proximate the renal artery to treat the patient's congestive heartfailure.

Energizing at least some of the bipolar electrode pairs may compriseusing a plurality of temperature sensors to adjust an energy output ofthe bipolar electrode pairs, each sensor positioned between one of thebipolar electrode pairs.

Positioning the expandable balloon in the renal artery of the patientmay comprise positioning an expandable balloon in which the bipolarelectrode pairs of the electrode assemblies are longitudinally offsetfrom circumferentially adjacent bipolar electrode pairs.

Another example method for treating a patient having congestive heartfailure may include positioning an expandable device including an arrayof energy delivery structures in a renal artery of the patient;expanding the expandable device such that at least some of the energydelivery structures are proximate a wall of the renal artery; andenergizing at least some of the energy delivery structures so as totherapeutically alter at least one nerve proximate the renal artery totreat the patient's congestive heart failure.

The energy delivery structures may be energized for less than tenminutes during the treatment, or the energy delivery structures may beenergized for less than five minutes during the treatment, or the energydelivery structures may be energized for less than one minute during thetreatment.

The energy delivery structures may be energized with the expandabledevice at only one position in the patient's renal artery during thetreatment.

An example method of treating congestive heart failure may includesubjecting a renal tissue of a patient to radio frequency energies forless than ten minutes such that the treatment is effective to reducenorepinephrine concentrations in the patient by greater than 50% inorder to treat the patient's congestive heart failure.

The treatment may be effective to reduce norepinephrine concentrationsproximate the renal tissue by greater than 50%.

Subjecting the renal tissue to radio frequency energies for less thanten minutes may comprise subjecting the renal tissue to radio frequencyenergies for less than five minutes.

Subjecting the renal tissue to radio frequency energies for less thanfive minutes comprises subjecting the renal tissue to radio frequencyenergies for less than one minute.

Subjecting the renal tissue to radio frequency energies may compriseraising a temperature proximate the renal tissue to a temperatureapproximately in the range of 50° C. to 80° C.

Raising the temperature to the temperature approximately in the range of50° C. to 80° C. may comprise raising the temperature to a temperatureapproximately in the range of 55° C. to 75° C. Raising the temperatureto the temperature approximately in the range of 55° C. to 75° C. maycomprise raising the temperature to a target temperature ofapproximately 68° C.

Raising the temperature to the target temperature of 68° C. may furthercomprise raising the temperature such that a rate of temperature changegradually decreases as the temperature approaches the targettemperature.

Raising the temperature such that the rate of temperature changegradually decreases as the temperature approaches the target temperaturemay comprise raising the temperature such that the rate of temperaturechange linearly decreases as the temperature approaches the targettemperature.

Subjecting the renal tissue to radio frequency energies may compriseinserting a catheter including a plurality of electrodes into a renalartery such that the electrodes are positioned proximate the renaltissue and selectively energizing the plurality of electrodes.

The congestive heart failure may be systolic congestive heart failure.

The congestive heart failure may be diastolic congestive heart failure.

An example renal-denervation treatment method may include delivering anRF energy treatment to a tissue proximate a renal artery using acatheter assembly of a renal denervation catheter system. Thedenervation system may include an RF energy generator coupled with thecatheter assembly by a controller. The method may also include applyingneural activity stimulation to the tissue proximate the renal arteryusing the catheter assembly; assessing stimulated neural activityresponse of the tissue using the catheter assembly; and determining aparameter of the RF energy treatment based on the assessed neuralactivity.

The method may also include outputting data relating to the assessedneural activity.

Outputting data may include outputting whether a sufficient decrease inneural activity has occurred.

Assessing the neural activity may include taking at least a first neuralactivity measurement and a second neural activity measurement.

Taking the first neural activity measurement may comprise taking thefirst neural activity measurement before beginning the delivery of theRF energy treatment to establish a base line neural activitymeasurement. Taking the second neural activity measurement may comprisetaking the second neural activity measurement after beginning thedelivery of the RF energy treatment. The method may also includedetermining whether neural activity has changed from the base line.

Determining whether neural activity has changed from the base line mayinclude determining whether the change in neural activity is at, aboveor below a threshold.

The method may also include terminating the RF energy treatment once thechange in neural activity is at or above the threshold.

Sensing stimulated neural activity response may comprise periodicallymeasuring for stimulated neural activity response during the RF energytreatment.

Applying neural activity stimulation may comprise energizing at leastone electrode of the catheter assembly. Assessing stimulated neuralactivity response may comprise using a second electrode of the catheterassembly to monitor for the nerve response signal.

Delivering the RF energy treatment may comprise using the at least oneelectrode and the second electrode to deliver RF energy to the tissue.

Delivering the RF energy treatment may comprise using the catheterassembly with the at least one electrode at a proximal end of anexpandable device and the second electrode at a distal end of thedevice.

Delivering the RF energy treatment may comprise using the catheterassembly with the at least one electrode and the second electrode beingat least one of laterally and circumferentially offset relative to oneanother.

Delivering the RF energy treatment may comprise using a plurality ofelectrodes other than the at least one electrode and the secondelectrode.

Monitoring for the nerve response signal may comprise at least one ofmeasuring an amplitude of the nerve response signal, measuring a timedelay between the nerve stimulation signal and the nerve responsesignal, and measuring a fractionated amplitude of the nerve responsesignal.

The method may also include measuring at least one of an amplitude ofthe nerve response signal, a pulse width of the nerve response signal, aslope or change in slope of the nerve response signal, a velocity of thenerve response signal, or a time delay of the nerve response signal.

The method may also include comparing the measurement to a base linemeasurement of an earlier nerve response signal.

Determining the at least one parameter of the RF energy treatment maycomprise adjusting the at least one parameter based on the assessedneural activity.

Adjusting the at least one parameter may comprise adjusting atemperature profile of the RF energy treatment.

Adjusting the at least one parameter may comprise adjusting a length oftime at a target temperature of the target temperature profile.

Adjusting the at least one parameter may comprise adjusting a voltagesetting of the RF energy generator.

Adjusting the at least one parameter may comprise adjusting the voltagesetting while maintaining a target temperature constant.

The method may also include terminating the RF energy treatment after apre-determined period of time if the assessed neural activity is notbelow a threshold level.

The method may also include repositioning the catheter assembly anddelivering a second RF energy treatment to a second tissue portionproximate the renal artery.

Determining the parameter of the RF energy treatment may furthercomprise determining the parameter of the RF energy treatment based onthe assessed neural activity and a temperature measurement of thetissue.

Another example renal-denervation method may include applying a firstneural activity stimulation to a tissue proximate a catheter assembly ofa renal denervation system; measuring a first stimulated neural activityresponse of the tissue using the catheter assembly; delivering an energytreatment to the tissue proximate the renal artery using the catheterassembly; measuring a second neural activity response of the neuraltissue using the catheter assembly; and determining a parameter of theenergy treatment by comparing the first and second measured neuralactivities.

Comparing the first and second measured neural activities may comprisecomparing at least one of a signal amplitude of the first and secondneural activities, a time delay associated with the first and secondneural activities, a pulse width of the first and second neuralactivities, a velocity of the first and second neural activities, and aslope or a change in slope of the first and second neural activities.

Another example denervation method may include delivering an energytreatment to a tissue proximate a body lumen using an implanted device;assessing a neural activity of the tissue using the implanted device;and determining, at least in part, at least one parameter of the energytreatment using the assessed neural activity.

Another example renal-denervation treatment method may includepositioning a catheter-based assembly in a renal artery, proximate abody tissue; delivering an energy treatment to the body tissue using thecatheter-based assembly; during or after the energy treatment, assessingwhether a neural activity level of the body tissue has decreased; andremoving the catheter-based assembly from the renal artery after asufficient decrease in the neural activity level.

The treatment may be effective to reduce norepinephrine concentrationsin a patient by greater than 50%.

The treatment may be effective to reduce norepinephrine concentrationsin the body tissue proximate the renal artery by greater than 50%.

The treatment may be effective to reduce a systolic blood pressure of apatient by at least 5%, or by at least 10%, or by at least 20%.

The treatment may be effective to reduce a diastolic blood pressure of apatient by at least 5%, or by at least 10%, or by at least 20%.

An example renal-denervation treatment system may include an elongatecatheter including an expandable structure at or near a distal end ofthe catheter. The expandable structure may include a plurality ofelectrodes. A power source may be electrically coupled to the pluralityof electrode. The system may also include a processor configured toenergize at least a subset of the electrodes at a renal-denervationenergy level, energize one or more of the electrodes at a neuralactivity stimulation level, and monitor for, using one or more of theelectrodes, a neural activity response.

The neural activity stimulation level may be a voltage in the range ofabout 0.1 V to about 5 V applied for about 1 second or less. Forexample, the neural activity stimulation level may be about 0.5 Vapplied for about 0.5 milliseconds.

The above summary of some embodiments is not intended to describe eachdisclosed embodiment or every implementation of the present disclosure.The Figures, and Detailed Description, which follow, more particularlyexemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a simplified schematic of an example system for remodelingtissue.

FIG. 1B is a perspective view of an example expandable device of acatheter.

FIG. 1C is a top view of the expandable device of FIG. 1B in an unrolledconfiguration.

FIGS. 1D and 1E are perspective views of example expandable devices.

FIG. 1F is a perspective view of an example expandable device.

FIG. 2A is a top view of an example electrode assembly.

FIG. 2B is partial cross-sectional view A-A of FIG. 2A.

FIG. 2C is partial cross-sectional view B-B of FIG. 2A.

FIGS. 3A-3D are top views of various example electrode assemblies havingmultiple electrode pads.

FIGS. 4A-4C are top views of various example electrode assemblies havingsingle distal electrode pads.

FIGS. 5A-5F are top views of various example electrode assemblies havingsingle proximal electrode pads.

FIGS. 5G-I are top views of various example monopolar electrodeassemblies.

FIG. 6 is a cross-sectional view of the system of FIG. 1A being used toremodel a body passageway.

FIGS. 7-10 illustrate various, non-limiting, examples of temperatureprofiles.

FIGS. 11 and 12 illustrate experimental results from a comparison ofcertain, non-limiting, examples of temperature profiles.

FIGS. 13 and 14 illustrate one embodiment of a control loop.

FIG. 13A illustrates another embodiment of a control loop.

FIG. 15 shows one non-limiting example of a change in temperature overtime for an electrode.

FIGS. 16-23 shows one non-limiting example of various attributesassociated with eight electrodes during a treatment.

FIGS. 24A-24F are example screen shots from one embodiment of atreatment.

FIGS. 25-30 illustrate one experiment assessing efficacy and safety ofan example system for renal denervation.

FIGS. 31 and 32 schematically illustrate example treatment zonesassociated with two electrodes.

FIG. 33 shows an expandable balloon including an electrode arraypositioned in a body passageway.

FIGS. 34-38 illustrate an experiment assessing, among other things, theextent of treatment zones created by electro-surgical procedures intissues proximate renal arteries.

FIGS. 39-41 illustrate an example of overlapping treatment zones duringthe course of an RF treatment.

FIGS. 42 and 43 schematically illustrate expandable device(s) of acatheter that include electrodes for stimulating and measuring nervesignals.

FIGS. 44 and 45 respectively illustrate a nerve response signalpre-treatment and after receiving at least some treatment.

FIG. 46 illustrates an embodiment of an expandable balloon.

FIGS. 47-50B illustrate embodiments of methods of renal denervationtreatments.

DETAILED DESCRIPTION

For the following defined terms, these definitions shall be applied,unless a different definition is given in the claims or elsewhere inthis specification.

All numeric values are herein assumed to be modified by the term“about,” whether or not explicitly indicated. The term “about” generallyrefers to a range of numbers that one of skill in the art would considerequivalent to the recited value (i.e., having the same function orresult). In many instances, the terms “about” may include numbers thatare rounded to the nearest significant figure.

The recitation of numerical ranges by endpoints includes all numberswithin that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and5).

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural referents unless the contentclearly dictates otherwise. As used in this specification and theappended claims, the term “or” is generally employed in its senseincluding “and/or” unless the content clearly dictates otherwise.

It is noted that references in the specification to “an embodiment”,“some embodiments”, “other embodiments”, etc., indicate that theembodiment described may include one or more particular features,structures, and/or characteristics. However, such recitations do notnecessarily mean that all embodiments include the particular features,structures, and/or characteristics. Additionally, when particularfeatures, structures, and/or characteristics are described in connectionwith one embodiment, it should be understood that such features,structures, and/or characteristics may also be used connection withother embodiments whether or not explicitly described unless clearlystated to the contrary.

The following detailed description should be read with reference to thedrawings in which similar elements in different drawings are numberedthe same. The drawings, which are not necessarily to scale, depictillustrative embodiments and are not intended to limit the scope of theinvention.

Physicians use catheters to gain access to and affect therapies byaltering interior tissues of the body, particularly within or about thelumens of the body such as blood vessels. For example, balloonangioplasty and other catheters often are used to open arteries thathave been narrowed due to atherosclerotic disease.

Catheters can be used to perform renal denervation by RF energytreatment in patients with refractory hypertension. This is a relativelynew procedure, which has been found to be clinically effective intreating hypertension. In the procedure, RF energy is applied to wallsof the renal artery to reduce hyper-activation (which is often the causeof chronic hypertension) of the sympathetic nervous system adjacent tothe renal artery. This procedure has been found to be successful in somecases, but also is associated with a significant amount of pain, andexisting treatments can be both relatively difficult for the physicianto accurately perform and quite time-consuming.

Another condition affecting many patients is Congestive Heart Failure(“CHF”). CHF is a condition which occurs when the heart becomes damagedand blood flow is reduced to the organs of the body. If blood flowdecreases sufficiently, kidney function becomes altered, which resultsin fluid retention, abnormal hormone secretions and increasedconstriction of blood vessels. These results increase the workload ofthe heart and further decrease the capacity of the heart to pump bloodthrough the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.For example, as the heart struggles to pump blood, the cardiac output ismaintained or decreased and the kidneys conserve fluid and electrolytesto maintain the stroke volume of the heart. The resulting increase inpressure further overloads the cardiac muscle such that the cardiacmuscle has to work harder to pump against a higher pressure. The alreadydamaged cardiac muscle is then further stressed and damaged by theincreased pressure. In addition to exacerbating heart failure, kidneyfailure can lead to a downward spiral and further worsening kidneyfunction. For example, in the forward flow heart failure describedabove, (systolic heart failure) the kidney becomes ischemic. In backwardheart failure (diastolic heart failure), the kidneys become congestedvis-a-vis renal vein hypertension. Therefore, the kidney can contributeto its own worsening failure.

The functions of the kidneys can be summarized under three broadcategories: filtering blood and excreting waste products generated bythe body's metabolism; regulating salt, water, electrolyte and acid-basebalance; and secreting hormones to maintain vital organ blood flow.Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of waste toxins in theblood and body. These conditions result from reduced renal function orrenal failure (kidney failure) and are believed to increase the workloadof the heart. In a CHF patient, renal failure will cause the heart tofurther deteriorate as fluids are retained and blood toxins accumulatedue to the poorly functioning kidneys. The resulting hypertension alsohas dramatic influence on the progression of cerebrovascular disease andstroke.

The autonomic nervous system is a network of nerves that affect almostevery organ and physiologic system to a variable degree. Generally, thesystem is composed of sympathetic and parasympathetic nerves. Forexample, the sympathetic nerves to the kidney traverse the sympatheticchain along the spine and synapse within the ganglia of the chain orwithin the celiac ganglia, then proceeding to innervate the kidney viapost-ganglionic fibers inside the “renal nerves”. Within the renalnerves, which travel along the renal hila (artery and to some extent thevein), are the post-ganglionic sympathetic nerves and the afferentnerves from the kidney. The afferent nerves from the kidney travelwithin the dorsal root (if they are pain fibers) and into the anteriorroot if they are sensory fibers, then into the spinal cord andultimately to specialized regions of the brain. The afferent nerves,baroreceptors and chemoreceptors, deliver information from the kidneysback to the sympathetic nervous system via the brain; their ablation orinhibition is at least partially responsible for the improvement seen inblood pressure after renal nerve ablation, or denervation, or partialdisruption. It has also been suggested and partially provenexperimentally that the baroreceptor response at the level of thecarotid sinus is mediated by the renal artery afferent nerves such thatloss of the renal artery afferent nerve response blunts the response ofthe carotid baroreceptors to changes in arterial blood pressure(American J. Physiology and Renal Physiology 279:F491-F501, 2000, thedisclosure of which is incorporated herein by reference).

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion which stimulates aldosterone secretion fromthe adrenal gland. Increased renin secretion can lead to an increase inangiotensin II levels, which leads to vasoconstriction of blood vesselssupplying the kidneys as well as systemic vasoconstriction, all of whichlead to a decrease in renal blood flow and hypertension. Reduction insympathetic renal nerve activity, e.g., via de-innervation, may reversethese processes and in fact has been shown to in the clinic.

As with hypertension, sympathetic nerve overdrive contributes to thedevelopment and progression of CHF. Norepinephrine spillover from thekidney and heart to the venous plasma is even higher in CHF patientscompared to those with essential hypertension. Chronic sympathetic nervestimulation overworks the heart, both directly as the heart increasesits output and indirectly as a constricted vasculature presents a higherresistance for the heart to pump against. As the heart strains to pumpmore blood, left ventricular mass increases and cardiac remodelingoccurs. Cardiac remodeling results in a heterogeneous sympatheticactivation of the heart which further disrupts the synchrony of theheart contraction. Thus, remodeling initially helps increase the pumpingof the heart but ultimately diminishes the efficiency of the heart.Decrease in function of the left ventricle further activates thesympathetic nervous system and the renin-angiotensin-aldosterone system,driving the vicious cycle that leads from hypertension to CHF.

Embodiments of the present disclosure relate to a power generating andcontrol apparatus, often for the treatment of targeted tissue in orderto achieve a therapeutic effect. In some embodiments, the target tissueis tissue containing or proximate to nerves, including renal arteriesand associated renal nerves. In other embodiments the target tissue isluminal tissue, which may further comprise diseased tissue such as thatfound in arterial disease.

In yet another exemplary embodiment of the present disclosure, theability to deliver energy in a targeted dosage may be used for nervetissue in order to achieve beneficial biologic responses. For example,chronic pain, urologic dysfunction, hypertension, and a wide variety ofother persistent conditions are known to be affected through theoperation of nervous tissue. For example, it is known that chronichypertension that may not be responsive to medication may be improved oreliminated by disabling excessive nerve activity proximate to the renalarteries. It is also known that nervous tissue does not naturallypossess regenerative characteristics. Therefore it may be possible tobeneficially affect excessive nerve activity by disrupting theconductive pathway of the nervous tissue. When disrupting nerveconductive pathways, it is particularly advantageous to avoid damage toneighboring nerves or organ tissue. The ability to direct and controlenergy dosage is well-suited to the treatment of nerve tissue. Whetherin a heating or ablating energy dosage, the precise control of energydelivery as described and disclosed herein may be directed to the nervetissue. Moreover, directed application of energy may suffice to target anerve without the need to be in exact contact, as would be required whenusing a typical ablation probe. For example, eccentric heating may beapplied at a temperature high enough to denature nerve tissue withoutcausing ablation and without requiring the piercing of luminal tissue.However, it may also be desirable to configure the energy deliverysurface of the present disclosure to pierce tissue and deliver ablatingenergy similar to an ablation probe with the exact energy dosage beingcontrolled by a power control and generation apparatus.

In some embodiments, efficacy of the denervation treatment can beassessed by measurement before, during, and/or after the treatment totailor one or more parameters of the treatment to the particular patientor to identify the need for additional treatments. For instance, adenervation system may include functionality for assessing whether atreatment has caused or is causing a reduction in neural activity in atarget or proximate tissue, which may provide feedback for adjustingparameters of the treatment or indicate the necessity for additionaltreatments.

While the disclosure focuses on the use of the technology in thevasculature, the technology would also be useful for other luminaltissues. Other anatomical structures in which the present disclosure maybe used are the esophagus, the oral cavity, the nasopharyngeal cavity,the auditory tube and tympanic cavity, the sinus of the brain, thearterial system, the venous system, the heart, the larynx, the trachea,the bronchus, the stomach, the duodenum, the ileum, the colon, therectum, the bladder, the ureter, the ejaculatory duct, the vas deferens,the urethra, the uterine cavity, the vaginal canal, and the cervicalcanal.

System Overview

FIG. 1A shows a system 100 for performing a treatment within a bodypassageway. The system 100 includes a control unit 110. The control unit110 can include an RF generator for delivering RF energy to catheterdevice 120. An exemplary control unit and associated energy deliverymethods useable with the embodiments disclosed herein are disclosed incommonly assigned U.S. Pat. App. Pub. No. US 2012/0095461, which isincorporated by reference herein. Further examples useable with theembodiments disclosed herein are disclosed in commonly assigned U.S.Pat. No. 7,742,795 entitled “Tuned RF Energy for Selective Treatment ofAtheroma and Other Target Tissues and/or Structures”, U.S. Pat. No.7,291,146 entitled “Selectable Eccentric Remodeling and/or Ablation ofAtherosclerotic Material”, and U.S. Pub. No. 2008/0188912 entitled“System for Inducing Desirable Temperature Effects on Body Tissue”, thefull disclosures of which are incorporated herein by reference. In someembodiments, particularly in some embodiments utilizing monopolar energydelivery, the system may also include a ground/common electrode, whichmay be associated with the catheter device, a separate pad that iselectrically coupled to the control unit 110, or otherwise associatedwith system 100.

In some embodiments, the control unit 110 may include a processor orotherwise be coupled to a processor to control or record treatment. Theprocessor will typically comprise computer hardware and/or software,often including one or more programmable processor units running machinereadable program instructions or code for implementing some, or all, ofone or more of the embodiments and methods described herein. The codewill often be embodied in a tangible media such as a memory (optionallya read only memory, a random access memory, a non-volatile memory, orthe like) and/or a recording media (such as a floppy disk, a hard drive,a CD, a DVD, a non-volatile solid-state memory card, or the like). Thecode and/or associated data and signals may also be transmitted to orfrom the processor via a network connection (such as a wireless network,an ethernet, an internet, an intranet, or the like), and some or all ofthe code may also be transmitted between components of a catheter systemand within the processor via one or more buses, and appropriate standardor proprietary communications cards, connectors, cables, and the likewill often be included in the processor. The processor may often beconfigured to perform the calculations and signal transmission stepsdescribed herein at least in part by programming the processor with thesoftware code, which may be written as a single program, a series ofseparate subroutines or related programs, or the like. The processor maycomprise standard or proprietary digital and/or analog signal processinghardware, software, and/or firmware, and may desirable have sufficientprocessing power to perform the calculations described herein duringtreatment of the patient, the processor optionally comprising a personalcomputer, a notebook computer, a tablet computer, a proprietaryprocessing unit, or a combination thereof. Standard or proprietary inputdevices (such as a mouse, keyboard, touchscreen, joystick, etc.) andoutput devices (such as a printer, speakers, display, etc.) associatedwith modern computer systems may also be included, and processors havinga plurality of processing units (or even separate computers) may beemployed in a wide range of centralized or distributed data processingarchitectures.

In some embodiments, control software for the system 100 may use aclient-server schema to further enhance system ease of use, flexibility,and reliability. “Clients” are the system control logic; “servers” arethe control hardware. A communications manager delivers changes insystem conditions to subscribing clients and servers. Clients “know”what the present system condition is, and what command or decision toperform based on a specific change in condition. Servers perform thesystem function based on client commands. Because the communicationsmanager is a centralized information manager, new system hardware maynot require changes to prior existing client-server relationships; newsystem hardware and its related control logic may then merely become anadditional “subscriber” to information managed through thecommunications manager. This control schema may provide the benefit ofhaving a robust central operating program with base routines that arefixed; no change to base routines may be necessary in order to operatenew circuit components designed to operate with the system.

Expandable Device and Electrode Assemblies

Returning to FIG. 1A, the catheter device 120 can include an expandabledevice 130, which can be a compliant, non-compliant, or semi-compliantballoon. The expandable device 130 includes a plurality of electrodeassemblies electrically coupled to the control unit 110. Such electrodeassemblies can be electrically configured to be monopolar or bipolar,and further have heat sensing capability.

As shown in FIG. 1B, the electrode assemblies may be arranged on theexpandable device 130, shown here in an expanded state, according to aplurality of cylindrical treatment zones A-D. In other embodiments, someof which are described further below, the expandable device 130 or othercomponents of the treatment system may include additional electrodeassemblies that are not in a treatment zone or are otherwise not used orconfigured to deliver a treatment energy.

The treatment zones A-D and associated electrode assemblies 140 a-d arefurther illustrated in FIG. 1C, which is an “unrolled” depiction of theexpandable device 130 of FIG. 1B. In some embodiments, the expandabledevice is a balloon with a 4 mm diameter and two electrode assemblies140 a-b. In other embodiments, the expandable device is a balloon with a5 mm diameter and three electrode assemblies 140 a-c. In someembodiments, the expandable device is a balloon with a 6, 7, or 8 mmdiameter and four electrode assemblies 140 a-d, as depicted in FIG. 1B.A 4 mm balloon having two electrode assemblies 140 a,b is shown in FIG.1D and a 5 mm balloon having three electrode assemblies 140 a-c is shownin FIG. 1E. For any of these configurations, the expandable device mayhave a working length of about 10 mm to about 100 mm, or about 18 mm toabout 25 mm, which is the approximate longitudinal span of all thetreatment zones A-D shown in FIGS. 1B and 1C. The electrode assemblies140 a-d can be attached to a balloon using adhesive.

FIG. 1F schematically illustrates an embodiment of an expandable devicethat includes an array of monopolar electrodes 190 (although, theelectrode arrays illustrated in FIGS. 1B through 1E and other figuresmay also be used in a monopolar configuration). In some instances, oneof the monopolar electrodes 190 on the expandable device may beconfigured to function as a common or ground electrode for the otherelectrodes. Alternatively, separate or differently shaped and configuredelectrodes on the expandable device (such as ring electrode 192illustrated in broken lines in FIG. 1F) or electrodes on otherexpandable devices (e.g. 194 in FIG. 1G) or otherwise associated withthe catheter may be configured as a common electrode. In still otherinstances, a grounding pad may be secured to the patient's skin tofunction as the common electrode. Although not shown explicitly in FIG.1G, the monopolar electrodes may each be positioned proximate or on atemperature sensing device, similar to other embodiments describedherein.

a. Overlapping and Non-Overlapping Treatment Zones

Returning to FIG. 1B, the treatment zones A-D are longitudinallyadjacent to one another along longitudinal axis L-L, and may beconfigured such that energy applied by the electrode assemblies createtreatments that do not overlap. Treatments applied by the longitudinallyadjacent bipolar electrode assemblies 140 a-d are circumferentiallynon-continuous along longitudinal axis L-L. For example, with referenceto FIG. 1C, lesions created in treatment zone A may in some embodimentsminimize overlap about a circumference (laterally with respect to L-L inthis view) with lesions created in treatment zone B.

In other embodiments, however, the energy applied by the electrodeassemblies, such as the electrode assemblies shown in FIG. 1C, mayoverlap, longitudinally, circumferentially, and/or in other ways, to atleast some extent. FIGS. 31 and 32 schematically illustrate non-limitingexamples of how electrodes 3102 and 3104 may be energized to createoverlapping treatment zones. Although not shown specifically in FIGS. 31and 32, electrodes 3102 and 3104 may each be a bipolar electrode pair(or may be single monopolar electrodes), and may be positioned on anouter surface of a catheter balloon or other expandable device such thatthey are longitudinally and circumferentially offset from one another(e.g. as in FIG. 1C). As shown in FIG. 31, each of electrodes 3102 and3104 may be associated with a treatment zone (or may be configured tocreate such a treatment zone in a tissue in apposition with theelectrodes) that includes a target temperature zone (the outer boundaryof which is labeled “TT”) and a thermal plume (the outer boundary ofwhich is labeled “TP”). In some embodiments, the target temperature zonerepresents a region of the tissue that is at or above a desired targettreatment temperature, or is within a desired target temperature range.In some embodiments, the thermal plume represents a region of the tissuethat is not necessarily at a target temperature or within a targettemperature range, but exhibits an increase in temperature relative toan untreated zone outside of the thermal plume.

Whether or not treatment zones between electrodes/electrode pairs willoverlap may be influenced by a wide variety of factors, including, butnot limited to, electrode geometry, electrode placement density,electrode positioning, ground/common electrode(s) placement and geometry(in monopolar embodiments), energy generator output settings, outputvoltage, output power, duty cycle, output frequency, tissuecharacteristics, tissue type, etc.

In some embodiments, individual electrodes of a bipolar electrode pairmay each define its own treatment zone, and such treatment zones maypartially or entirely overlap.

In FIG. 31, the thermal plumes of the treatment zones overlap, althoughthe target temperature zones do not. In FIG. 32, both the targettemperature zones and the thermal plumes overlap. In some embodiments,the overlap of treatment zones may extend substantially continuouslyaround a circumference of the device and/or around a circumference in atissue surrounding a body passageway. In other embodiments, there may beoverlap in treatment zones, however, that overlap will not besubstantially continuous around a circumference and significantdiscontinuities in the treatment zones may be present.

It has been experimentally determined that at least some electrosurgicalsystems utilizing an array of balloon-mounted electrodes can createoverlapping treatment zones between adjacent electrode pads, and, in atleast some instances, create treatment zones that are effectivelysubstantially continuous about a circumference of a body passageway. Inone experiment, a catheter and expandable balloon similar to that shownand described in U.S. Pub. No. 2008/0188912 (incorporated in itsentirety by this reference), particularly at FIG. 9C (reproduced here asFIG. 33), was used to generate overlapping treatment zones betweenadjacent electrode pairs, such that a treatment zone effectivelyextended substantially continuously about a circumference. As shown inFIG. 33, the expandable balloon 20 includes several longitudinallyextending series of bipolar electrode pairs 34 positioned about thecircumference of the balloon. Unlike the electrode arrays shown in, forinstance, FIG. 1C, the electrode arrays shown in FIG. 33 are arrangedsymmetrically on the expandable balloon 20.

In one experiment utilizing a catheter-based balloon electrode arraysimilar to that of FIG. 33, local response of fourteen renal vesselsthat were either treated with various power and duration ofradio-frequency regimens (about 60° C. to about 75° C. for about 5seconds to about 120 seconds), or left untreated, was evaluated on day28±1 and day 84. Additionally, the kidneys from a total of 7 animalswere evaluated via light microscopy. Kidneys and renal arteries wereexplanted intact with underlying muscle and fixed in 10% neutralbuffered formalin. Fixed tissues were then submitted forhistopathological processing and evaluation. Each vessel was trimmed atapproximately every 3-4 mm until the tissue was exhausted, processed,embedded in paraffin, sectioned twice at ˜5 microns, and stained withhematoxylin and eosin (H+E) and elastin trichrome (ET). Kidneys weretrimmed at three levels (cranial, center and caudal), processed,embedded in paraffin, sectioned and stained with H+E. All resultingslides were examined via light microscopy.

Evaluation of step sections from six acute arteries treated at variouspower and duration of radio-frequency regimens or left untreated, andevaluation of dependent kidneys showed acute thermal changescharacterized by coagulation necrosis in the media and perivasculartissues and collagen hyalinization. FIG. 34 shows a cross section of aleft renal artery (labeled A) and surrounding tissue treated with sixpairs of electrodes in a 75° C. protocol for ten seconds. In FIG. 34,circumferential thermal injury was observed within the boundaries of thedotted line, including injury to several nerve branches (as indicated bythe arrowheads), a ganglion (short arrow) and a portion of the adjacentlymph node (LN). FIG. 35 shows a cross section of a right renal arteryand surrounding tissue treated with six pairs of electrodes in a 75° C.protocol for five seconds. In FIG. 35, circumferential injury wasobserved within the boundaries of the dotted line and includes severalnerve branches (as indicated by the arrowheads). Referring to FIGS. 34and 35, thermal injury was circumferential in the central-most segmenttreated in the left artery and in the media of the right artery. Thekidneys showed no treatment-related changes. Circumferential treatmentwas effective at reaching and creating injury in extrinsic renalinnervation with a radial reach that was up to 10 mm in depth. There wasminimal to notable procedural injury caused by balloon treatment of amagnitude likely to trigger a significant restenotic response.

FIGS. 36 and 37 show additional cross sections of the left renal arteryof FIG. 34, at day 27 post treatment. FIG. 38 is another representativelow magnification image of a 75° C. RF treatment. The zones of treatmentin FIG. 38 are evidenced by residual necrotic tunica media andadventitial thickening by early smooth muscle cell hyperplasia,fibroplasia, and inflammatory infiltrates (e.g., brackets). FIG. 38 alsoshows extension of the zone of treatment into the adjacent adventitia(as shown by the dashed lines).

FIGS. 39-41 further illustrates how, in some embodiments, treatmentzones can overlap over the course of an RF energy treatment. FIGS. 39-41illustrate a Vessix V2 catheter positioned in a cylinder filled with athermo-sensitive gel over the course of a thirty second treatment. FIG.39 shows the thermo-sensitive gel just after treatment initiation, withthe square shaped patches in the gel indicating localized electrodeheating. As shown in FIG. 40, as the treatment progresses, the patchesin the gel increase in size due to heat conduction and come close totouching. FIG. 41 shows the gel at the completion of a 30 secondtreatment, showing substantial overlap in the patches.

b. Electrode Assembly Structure

Returning to FIG. 1C, each electrode pad assembly includes four majorelements, which are a distal electrode pad 150 a-d, intermediate tail160 a-d, proximal electrode pad 170 a-d, and proximal tail 180 b,d (notshown for electrode pad assemblies 140 b and 140 c). Constructionaldetails of the electrode assemblies 140 a-d are shown and described withreference to FIGS. 2A-C.

FIG. 2A shows a top view of electrode assembly 200, which is identifiedin FIG. 1C as electrode assembly 140. The electrode assembly 200 isconstructed as a flexible circuit having a plurality of layers. Suchlayers can be continuous or non-contiguous, i.e., made up of discreteportions. Shown in FIGS. 2B and 2C, a base layer 202 of insulationprovides a foundation for the electrode assembly 200. The base layer 202can be constructed from a flexible polymer such as polyimide. In someembodiments, the base layer 202 is approximately 0.5 mil (0.0127 mm)thick. A conductive layer 204 made up of a plurality of discrete tracesis layered on top of the base layer 202. The conductive layer 204 canbe, for example, a layer of electrodeposited copper. In someembodiments, the conductive layer 204 is approximately 0.018 mm thick.An insulating layer 206 is discretely or continuously layered on top ofthe conductive layer 204, such that the conductive layer 204 is fluidlysealed between the base layer 202 and the insulating layer 206. Like thebase layer 202, the insulating layer 206 can be constructed from aflexible polymer such as polyimide. In some embodiments, the insulatinglayer 206 is approximately 0.5 mil (0.0127 mm) thick. In otherembodiments, the insulating layer 206 is a complete or partial polymercoating, such as PTFE or silicone.

The electrode assembly 200 shown in FIG. 2A includes a distal electrodepad 208. In this region, the base layer 202 forms a rectangular shape.As shown, the electrode assembly 200 may include a plurality of openingsto provide for added flexibility, and the pads and other portions of theassemblies may include rounded or curved corners, transitions and otherportions. In some instances, the openings and rounded/curved featuresmay enhance the assembly's resistance to delamination from itsexpandable device, as may occur, in some instances, when the expandabledevice is repeatedly expanded and collapsed (which may also entaildeployment from and withdrawal into a protective sheath), such as may beneeded when multiple sites are treated during a procedure.

The distal electrode pad 208 includes a plurality of discrete traceslayered on top of the base layer 202. These traces include a groundtrace 210, an active electrode trace 212, and a sensor trace 214. Theground trace 210 includes an elongated electrode support 216 laterallyoffset from a sensor ground pad 218. The sensor ground pad 218 iselectrically coupled to the elongated support 216 of the ground trace210 and is centrally located on the distal electrode pad 208. A bridge220 connects a distal most portion of the sensor ground pad 218 to adistal portion of the elongated electrode support 216 of the groundtrace 210. The bridge 220 tapers down in width as it travels to thesensor ground pad 218. In some embodiments, the bridge 220 has arelatively uniform and thin width to enable a desired amount offlexibility. The elongated electrode support 216 tapers down in width atits proximal end, however, this is not required. In some embodiments,the elongated electrode support 216 can abruptly transition to a muchthinner trace at its proximal portion, to enable a desired amount offlexibility. Generally, the curvature of the traces where necking isshown is optimized to reduce balloon recapture forces and the potentialfor any snagging that sharper contours may present. The shape andposition of the traces are also optimized to provide dimensionalstability to the electrode assembly 200 as a whole, so as to preventdistortion during deployment and use.

The ground trace 210 and active electrode trace 212 of FIG. 2A share asimilar construction. The active electrode trace 212 also includes anelongated electrode support 216.

FIG. 2B shows a partial cross-section A-A of the distal electrode pad208. An electrode 222 is shown layered over a portion of the insulatinglayer 206, which has a plurality of passages (e.g., holes) to enable theelectrode 222 to couple to the elongated electrode support 216 of theground trace 210 (of conductive layer 204).

As shown in FIG. 2A, the ground electrode trace 210 and active electrodetrace 212 can include a plurality of electrodes. Three electrodes 222are provided for each electrode trace, however, more or less can beused. Additionally, each electrode 222 can have radiused corners toreduce tendency to snag on other devices and/or tissue. Although theabove description of the electrodes 222 and the traces associated withthem has been described in the context of a bi-polar electrode assembly,those of skill in the art will recognize that the same electrodeassembly may function in a monopolar mode as well. For instance, as onenon-limiting example, the electrodes associated with active electrodetraces 212 and 242 may be used as monopolar electrodes, with groundtrace 210 disconnected during energization of those electrodes.

It has been experimentally determined that an example embodiment for arenal hypertension indication having an approximate longitudinal lengthof 4 mm per plurality of electrodes, including longitudinal spacingbetween electrodes 222, provides effective tissue remodeling resultswith respect to optimal lesion size and depth, while avoiding a stenoicresponse. The shown configuration was arrived at by balancing depth ofthermal penetration, and avoidance of thermal damage to tissuecollateral the treatment zone, while seeking to minimize the number ofelectrode pairs to optimize flexibility and profile on a final deviceHowever, the shown configuration is not a necessary requirement, sinceelectrode size and placement geometry can vary according to desiredtherapeutic effect.

Thirty-three Yorkshire swine were subjected to renal denervation (RDN)by Vessix Vascular's renal denervation radiofrequency (RF) ballooncatheters. Putative renal denervation through Vessix Vascular'selectrode design was accomplished through a spectrum of settings (afunction of electrode length, temperature, and duration) to compare thesafety at 7 days and 28 days post-procedure between Vessix 16 mmcircumferential electrodes vs. 2 mm and 4 mm electrode with offsetdesign. Histologic sections of the renal arteries were examined toevaluate the tissue response including, but not limited to: injury,inflammation, fibrosis, and mineralization at 7 and 28 days.

The treatment of renal arteries with the Vessix Vascular RDN RF BalloonCatheter resulted in a spectrum of changes in the arterial wall andadjacent adventitia, which represented the progression of thearterial/adventitial response from an acute, “injurious” phase to achronic, “reactive/reparative” phase. Treated areas within the renalarteries were apparent due to the presence of these changes in thearterial wall and extension thereof into the adjacent adventitial tissue(interpreted as the “zone of treatment”).

At Day 7, all electrodes, regardless of length, treatment temperature orduration were associated with a primarily injurious response. However,the 2 mm and 4 mm electrodes were also associated with an earlyreactive/reparative response, regardless of treatment duration, whichwas not observed with either 16 mm RF treatment at Day 7. The overallextent of arterial circumference affected with the 16 mm electrodes wasincreased (mild/moderate to marked, ˜>75% to 100% of circumferencecovered, respectively), regardless of temperature, relative to theshorter electrodes (2 mm and 4 mm) in which the affect was typicallyminimal to mild/moderate (˜<25% to ˜25-75% circumference affected,respectively), regardless of duration of treatment.

At Day 28, frequent, minimal neointima formation was observed,regardless of time point, in all treatment groups with the exception ofthe shorter 4 mm electrode. Mild/moderate neointima formation wasinfrequently observed only at Day 28, regardless of treatment group;however, the 16 mm electrodes were associated with a mild and comparableincrease in the incidences of mild/moderate neointima relative to theshorter 2 and 4 mm electrode.

The denudation (i.e., loss) of endothelial cells is a common sequelae tothe passage of any interventional device as well as an expected sequelaeto the treatment with the Vessix Vascular RDN RF Balloon Catheter. Dueto the importance of the endothelium in preventing thrombus formation,its recovery in denuded regions was monitored. As such, themagnitude/extent of the re-endothelialization of the luminal surface wasinterpreted relative to the approximate circumference of the arteryaffected

At Day 7, the 2 and 4 mm electrodes had more arterial sections withcomplete endothelialization than not; complete endothelialization waspresent in all arterial sections of the 2 and 4 mm electrode. Noarterial section treated with a 16 mm electrode was observed to havecomplete endothelialization at Day 7, regardless of dose.

At Day 7, inflammation was overall typically minimal, regardless oftreatment; however, both 16 mm electrodes, regardless of dose, had anoverall increase in inflammation relative to 2 and 4 mm electrodes.Mild/moderate inflammatory infiltrates were rarely observed in the 2 and4 mm electrode, but were frequent to common in the 16 mm electrodes.

In the embodiment of FIG. 2A, each electrode 222 is approximately 1.14mm by 0.38 mm, with approximately 0.31 mm gaps lying between theelectrodes 222. The electrodes 222 of the ground trace 210 and activeelectrode trace 212 are laterally spaced by approximately 1.85 mm. Insome embodiments, such as the embodiment shown in FIG. 2B, theelectrodes 222 are gold pads approximately 0.038 mm thick from theconductive layer 204 and that protrude 0.025 mm above the insulatinglayer 206. Without limiting the use of other such suitable materials,gold is a good electrode material because it is very biocompatible,radiopaque, and electrically and thermally conductive. In otherembodiments, the electrode thickness of the conductive layer 204 canrange from about 0.030 mm to about 0.051 mm. At such thicknesses,relative stiffness of the electrodes 222, as compared to, for example,the copper conductive layer 204, can be high. Because of this, using aplurality of electrodes, as opposed to a single electrode, can increaseflexibility. In other embodiments, the electrodes may be as small as 0.5mm by 0.2 mm or as large as 2.2 mm by 0.6 mm for electrode 222.

While it is an important design optimization consideration to balancethe thickness of the gold above the insulating layer 206 so as toachieve good flexibility while maintaining sufficient height so as toprovide good tissue contact, this is counterbalanced with the goal ofavoiding a surface height that may snag during deployment or collapse ofthe balloon. These issues vary according to other elements of aparticular procedure, such as balloon pressure. For many embodiments, ithas been determined that electrodes that protrude approximately 0.025 mmabove the insulating layer 206 will have good tissue contact at ballooninflation pressures below 10 atm and as low as 2 atm. These pressuresare well below the typical inflation pressure of an angioplasty balloon.

The sensor trace 214 is centrally located on the distal electrode pad208 and includes a sensor power pad 224 facing the sensor ground pad218. These pads can connect to power and ground poles of a heat sensingdevice 226, such as a thermocouple (for example, Type T configuration:Copper/Constantan) or thermistor, as shown in the partial cross-sectiondepicted in FIG. 2C.

The heat sensing device 226 is proximately connected to the sensor powerpad 224 and distally connected to the sensor ground pad 218. To helpreduce overall thickness, the heat sensing device 226 is positionedwithin an opening within the base layer 202. In some embodiments, theheat sensing device 226 is a thermistor having a thickness of 0.1 mm,which is unusually thin—approximately two-thirds of industry standard.As shown, the heat sensing device 226 is on a non-tissue contacting sideof the distal electrode pad 208. Accordingly, the heat sensing device226 is captured between the electrode structure and a balloon whenincorporated into a final device, such as catheter 120. This isadvantageous since surface-mounted electrical components, likethermistors, typically have sharp edges and corners, which can getcaught on tissue and possibly cause problems in balloon deploymentand/or retraction. This arrangement also keeps soldered connections frommaking contact with blood, since solder is typically non-biocompatible.Further, due to the placement of the heat sensing device, it can measuretemperature representative of tissue and the electrodes 222. Designs inthe prior art typically take one of two approaches—either contactingtissue or contacting the electrode. Here, neither of these priorapproaches are employed.

From the rectangular distal electrode pad 208, the combined base layer202, conductive layer 204, and insulating layer 206 reduce in lateralwidth to an intermediate tail 228. Here, the conductive layer 204 isformed to include an intermediate ground line 230, intermediate activeelectrode line 232, and intermediate sensor line 234, which arerespectively coextensive traces of the ground trace 210, activeelectrode trace 212, and sensor trace 214 of the distal electrode pad208.

From the intermediate tail 228, the combined base layer 202, conductivelayer 204, and insulating layer 206 increase in lateral width to form aproximal electrode pad 236. The proximal electrode pad 236 isconstructed similarly to the distal electrode pad 208, with theelectrode geometry and heat sensing device arrangement being essentiallyidentical, although various differences may be present. However, asshown, the proximal electrode pad 236 is laterally offset from thedistal electrode pad 208 with respect to a central axis G-G extendingalong the intermediate ground line 230. The intermediate activeelectrode line 232 and intermediate sensor line 234 are laterallycoextensive with the proximal electrode pad 236 on parallel respectiveaxes with respect to central axis G-G.

From the proximal electrode pad 236, the combined base layer 202,conductive layer 204, and insulating layer 206 reduce in lateral widthto form a proximal tail 238. The proximal tail 238 includes a proximalground line 240, proximal active electrode line 242, and proximal sensorline 244, as well the intermediate active electrode line 232 andintermediate sensor line 234. The proximal tail 238 includes connectors(not shown) to enable coupling to one or more sub-wiring harnessesand/or connectors and ultimately to control unit 110. Each of theselines are extended along parallel respective axes with respect tocentral axis G-G.

As shown, the electrode assembly 200 has an asymmetric arrangement ofthe distal electrode pad 208 and proximal electrode pad 236, about axisG-G. Further, the ground electrodes of both electrode pads aresubstantially aligned along axis G-G, along with the intermediate andproximal ground lines 230/240. It has been found that this arrangementpresents many advantages. For example, by essentially sharing the sameground trace, the width of the proximal tail is only about one and ahalf times that of the intermediate tail 228, rather than beingapproximately twice as wide if each electrode pad had independent groundlines. Thus, the proximal tail 238 is narrower than two of theintermediate tails 228.

Further, arranging the electrode pads to share a ground trace allowscontrol of which electrodes will interact with each other. This is notimmediately apparent when viewing a single electrode assembly, butbecomes evident when more than one electrode assembly 200 is assembledonto a balloon, for example as shown in FIG. 1C. The various electrodepads can be fired and controlled using solid state relays andmultiplexing with a firing time ranging from about 100 microseconds toabout 200 milliseconds or about 10 milliseconds to about 50milliseconds. For practical purposes, the electrode pads appear to besimultaneously firing yet stray current between adjacent electrode padsof different electrode assemblies 200 is prevented by rapid firing ofelectrodes in micro bursts. This can be performed such that adjacentelectrode pads of different electrode pad assemblies 200 are fired outof phase with one another. Thus, the electrode pad arrangement of theelectrode assembly allows for short treatment times—10 minutes or lessof total electrode firing time, with some approximate treatment timesbeing as short as 10 seconds, with and exemplary embodiment being about30 seconds. The benefits of short treatment times include minimizationof post-operative pain caused when nerve tissue is subject to energytreatment, shortened vessel occlusion times, reduced occlusion sideeffects, and quick cooling of collateral tissues by blood perfusion dueto relatively minor heat input to luminal tissue.

In some embodiments, the common ground typically carries 200 VAC at 500kHz coming from the negative electrode pole, and a 1V signal from theheat sensing device 226 (in the case of a thermistor) that requiresfiltering of the RF circuit such that the thermistor signal can besensed and used for generator control. In some embodiments, because ofthe common ground, the thermistor of the adjacent electrode pair may beused to monitor temperature even without firing the adjacent electrodepair. This provides the possibility of sensing temperatures proximate toboth the distal electrode pad 208 and the proximal electrode pad 236,while firing only one of them.

Referring again to FIG. 1C, the electrode pad arrangement of eachelectrode assembly 140 a-d also enables efficient placement on balloon130. As shown, the electrode assemblies 140 a-d “key” into one anotherto enable maximum use of balloon surface area. This is accomplished inpart by spacing the electrode pads apart by setting the longitudinallength of each intermediate tail. For example, the intermediate taillength electrode assembly 140 a is set to a distance that separates itsdistal and proximal electrode pads 150 a,170 a such that the laterallyadjacent proximal electrode pad 170 b of the laterally adjacentelectrode assembly 140 b keys next to the intermediate tail 160 a ofelectrode assembly 140 a. Further, the distal electrode pad 150 a ofelectrode assembly 140 a is keyed between the intermediate tail 160 b ofelectrode assembly 140 b and the intermediate tail 160 d of electrodeassembly 140 d. Thus, the length of each intermediate tail 160 a-d alsorequires each electrode pad of any one electrode assembly to be locatedin non-adjacent treatment zones.

Balloon surface area maximization is also enabled in part by laterallyoffsetting both electrode pads of each electrode assembly 140 a-d. Forexample, the rightwards lateral offset of each distal electrode pad 150a-d and the leftwards lateral offset of the proximal electrode pad 170a-d allow adjacent electrode pad assemblies to key into one another suchthat some of the electrode pads laterally overlap one another. Forexample, the distal electrode pad 150 a of electrode assembly 140 alaterally overlaps with proximal electrode pad 170 b of electrodeassembly 140 b. Further, the distal electrode pad 150 b of electrodeassembly 140 b laterally overlaps with the proximal electrode pad 170 cof electrode assembly 140 c. However, the length of each intermediatetail prevents circumferential overlap (longitudinal overlap in thisview) of the electrode pads, thus maintaining the non-contiguous natureof the treatment zones in the longitudinal direction L-L.

The arrangement and geometry of the electrode pads, as well as thearrangement and geometry of the tails of the flexible circuits may alsofacilitate folding or otherwise collapsing the balloon into a relativelycompact un-expanded state. For instance, in embodiments with an expandeddiameter of up to 10 mm, the device in an un-expanded state may have aslow as an approximately 1 mm diameter.

Some embodiments utilize a standard electrode assembly having identicaldimensions and construction, wherein the number and relative position ofelectrode assemblies on an outer surface of a balloon becomes a functionof balloon diameter and/or length while electrode assembly geometriesremain unchanged amongst various balloon sizes. The relative positioningof electrode assemblies relative to balloon diameter and/or length maythen be determined by the desired degree or avoidance of circumferentialand/or axial overlap of adjacent electrode pads of neighboring electrodeassemblies on a balloon of a given size. In other embodiments, however,all of the electrode assemblies on the balloon will not necessarily beidentical.

FIGS. 3A-3D shows alternative electrode pad configurations useable withthe system 100 of FIG. 1A. FIG. 3A shows an electrode assembly 300 thatis constructed similarly to electrode assembly 200, but having twoelectrode pads 302 that are directly adjacent to one another.

FIG. 3B shows an electrode pad assembly 304 that is constructedsimilarly to electrode assembly 200, but having two electrode pads 306that are directly adjacent to one another. Further, the electrode pads306 have electrodes arranged to be transverse with respect tolongitudinal axis L-L of FIGS. 1C and G-G of FIG. 2A.

FIG. 3C shows an electrode assembly 310 that is constructed similarly toelectrode assembly 304, but having three staggered and separatedelectrode pads 312. Like the electrode assembly 304 of FIG. 3B, theelectrode pads 312 feature transversely arranged electrodes.

FIG. 3D shows an electrode assembly 314 that is constructed similarly toelectrode assembly 310, but having electrode pads 312 with greaterelectrode surface area. Like the electrode assembly 304 of FIG. 3B, theelectrode pads 316 feature transversely arranged electrodes.

FIGS. 4A-4C shows alternative electrode pad configurations useable withthe system 100 of FIG. 1A. FIG. 4A shows an electrode assembly 400 thatis constructed similarly to electrode assembly 200, but having only asingle distal electrode pad 402.

FIG. 4B shows an electrode assembly 404 that is constructed similarly toelectrode assembly 400, but having an single distal electrode pad 407with a greater active electrode 408 surface area than ground surfacearea 410.

FIG. 4C shows an electrode assembly 412 that is constructed similarly toelectrode assembly 404, but having a single distal electrode pad 414having a heavily porous construction to enable greater flexibility.

FIGS. 5A-5F shows alternative electrode configurations useable with thesystem 100 of FIG. 1A. In some embodiments, the shown electrodeconfigurations are useable with the configurations of FIGS. 4A-4C. FIG.5A shows an electrode assembly 500 that is constructed similarly toelectrode assembly 400, but arranged to include only a single proximalelectrode pad 502. The electrode assembly 500 further includes anelongated distal portion 504 for attachment to a balloon.

FIG. 5B shows an electrode assembly 506 that is constructed similarly toelectrode assembly 500, but having more comparative electrode surfacearea on electrode pad 508.

FIG. 5C shows an electrode assembly 510 that is constructed similarly toelectrode assembly 500, but having more comparative electrode surfacearea on electrode pad 512 and a larger number of electrodes.

FIG. 5D shows an electrode assembly 514 that is constructed similarly toelectrode assembly 510, but having a non-uniform electrode configurationon electrode pad 512.

FIG. 5E shows an electrode assembly 514 that is constructed similarly toelectrode assembly 500, but having less comparative electrode surfacearea on electrode pad 516 and a smaller number of electrodes 518.Electrode pad 516 also incorporates two heat sensing devices 520 mountedon the same side as electrodes.

FIG. 5F shows an electrode assembly 522 that is constructed similarly toelectrode assembly 514, but having a transversely arranged electrode 524and a single heat sensing device 526.

The electrode assemblies of FIGS. 2 through 5F may be used in bipolar ormonopolar configurations. FIGS. 5G through 5I illustrate additionalexamples of monopolar electrode configurations. In FIG. 5G there are twoparallel arrays of monopolar electrodes 530 on either side oftemperature sensor 532. In FIG. 5G, each array of monopolar electrodes530 has its own discrete trace, with the temperature sensor 532 havingits own discrete trace as well. In other embodiments, however, all ofthe monopolar electrodes 530 on a particular flex circuit assembly mayshare a single active trace, and one of the temperature sensor's twotraces may be shared as well, although, in other embodiments, the powerand ground traces for the temperature sensor may be separate from themonopoloar trace(s).

FIG. 5H illustrates another arrangement for a monopolar electrode pad inwhich all of the monopolar electrodes 536 are coupled to a single trace.FIG. 5I shows another alternative arrangement for the monopolarelectrodes and temperature sensor. The monopolar electrode pads may bearranged about an expandable device in longitudinally andcircumferentially offset arrangements (such as shown in FIG. 1C) and mayhave geometries and arrangements similar to those shown in FIGS. 3Athrough 5F.

Treatment Methods and Control Systems

a. Device Positioning

FIG. 6 shows the system 100 of FIG. 1A being used to perform a method600 of treatment in accordance with one non-limiting embodiment of thedisclosure. Here, control unit 110 is shown operationally coupled tocatheter device, which has been placed in a body passageway such that anexpandable device (having a plurality of electrode assemblies) is placedadjacent to a section 51 of the body passageway where therapy isrequired. Placement of the catheter device at section 51 can beperformed according to conventional methods, e.g., over a guidewireunder fluoroscopic guidance. Once placed in S1, the expandable devicecan be made to expand, e.g., by pressurizing fluid from 2-10 atm in thecase of a balloon. This causes electrodes of the expandable device tocome into contact with the body passageway.

In some embodiments, control unit 110 may measure impedance at theelectrode assemblies to confirm apposition of the electrodes with thebody passageway. In at least some of these embodiments, the treatmentmay proceed even if apposition is not sensed for all of the electrodes.For instance, in some embodiments, the treatment may proceed ifapposition is sensed for 50% or more of the electrodes, and may allowfor less than complete uniformity of apposition circumferentially and/oraxially. For example, in some instances the catheter may be positionedsuch that one or more of the proximal electrodes are in the aorta andexposed to blood, and impedance sensed for such electrodes may not fallwithin a pre-designated range (such as, for example, 500-1600 ohms),indicating an absence of tissue apposition for those electrodes. In someinstances, the system may allow for user authorization to proceed withthe treatment even if there is less than uniform electrode/tissueapposition. Subsequently, the control unit 110 may activate theelectrodes to create a corresponding number of lesions L, as indicatedby the black squares. During activation of the electrodes, the controlunit uses heat sensing devices of the electrode pads to monitor bothheat of the electrode and the tissue due to the unique arrangement ofthe heat sensing devices, which do not contact either tissue orelectrodes. In this manner, more or less power can be supplied to eachelectrode pad as needed during treatment.

In some embodiments, control unit 110 may apply a uniform standard fordetermining apposition to all the electrodes of the device. Forinstance, the control unit may utilize the same pre-designated range ofresistance measurements to all of the electrodes. In other instances,however, including some, although not all, monopolar applications,different standards may be applied to different monopolar electrodes fordetermining apposition. For example, in some monopolar embodiments, eachmonopolar electrode may define a discrete electrical circuit through thetissue to the common/indifferent electrode (or electrodes), and thecharacteristics of those circuits (e.g. resistance) may varysignificantly based on the distance between the monopolar electrode andcommon electrode, the tissue characteristics therebetween, and othergeometries and characteristics of the device and surrounding tissue. Assuch, in at least some embodiments, it may be desirable to applycriteria for determining apposition that varies depending on, e.g., thedistance between the monopolar electrode and common electrode (e.g. thegreater the distance between the two electrodes, the higher theimpedance measurement required to determine good apposition). In otherembodiments, however, the variance due to these differences in distanceand other geometries will be minimal or non-substantive, and a uniformstandard may be applied.

FIGS. 24A-F illustrate one non-limiting example of a series of screenshots displayed by the control unit during the course of a treatment. InFIG. 24A, the system prompts a user to connect a catheter. In FIG. 24B,the system confirms that a catheter has been connected and otherinformation about the connected catheter (e.g. size/diameter). At FIGS.24C and D, the system, as discussed above, can check for electrodeapposition, indicate which or what number of electrodes are inapposition, and ask for authorization to proceed. In FIG. 24C, threeelectrodes (e.g., the first three or “proximal” electrodes) are shown asin apposition while in FIG. 24D all the electrodes are shown inapposition.

In FIGS. 24E and F, the system may display certain parameters of thetreatment, both during and after the treatment (e.g. power, temperature,time, and number of active/activated electrodes). Information about thetreatment, such as the aforementioned parameters and/or otherinformation, may be captured by the system and saved to memory.

Returning to FIG. 6, after the prescribed therapy in section 51 iscomplete, the expandable device may then be deflated and moved to anuntreated section S2 to repeat the therapy applied in section 51, andsimilarly to section S3, and any more sections as needed. The sectionsare shown directly adjacent, but can be separated by some distance.

In some instances, alternative methods other than those illustrated inFIG. 6 will be utilized. For instance, in other embodiments, thetreatment will be performed at only a single location in the passageway,and it will not be necessary to move the expandable device to multiplelocations in the passageway.

Referring again to the example of renal hypertension involving thereduction of excessive nerve activity, the system may be used to effecta non-piercing, non-ablating way to direct energy to affect nerveactivity. Accordingly the body passage shown can be a renal arterysurrounded by nerve tissue N in sections S1-S3. Electrodes on theexpandable device may be powered to deliver energy in the knowndirection of a nerve N to be affected, the depth of energy penetrationbeing a function of energy dosage, electrode type (e.g. monopolar vs.bipolar) and electrode geometry. U.S. Pub. No. 2008/0188912 entitled“System for Inducing Desirable Temperature Effects on Body Tissue”, thefull disclosure of which is incorporated herein by reference, describessome considerations for electrode geometry and the volume of tissuetreatment zones that may be taken into account in some, although notnecessarily all, embodiments. In some instances, empirical analysis maybe used to determine the impedance characteristics of nervous tissue Nsuch that catheter device may be used to first characterize and thentreat tissue in a targeted manner as disclosed and described herein. Thedelivery and regulation of energy may further involve accumulated damagemodeling as well.

As shown, each lesion L is created in a corresponding treatment zone A-Dof the expandable device 130. Accordingly, any lesion L made in oneparticular treatment A-D zone will not circumferentially overlap with alesion of an adjacent treatment zone A-D at any point along theoperational axis O-O. In some embodiments, a treatment zone of theexpandable device 130 can have more than one electrode pad, and thus insuch cases, lesions L created by those electrode pads cancircumferentially overlap. In those cases, more lesions L may berequired for a particular anatomy or a pair of electrode pads arerequired for performing a diagnostic routine before therapy is applied.Regardless, circumferential overlap of electrodes of adjacent treatmentzones will not be present.

b. Energy Delivery

Depending on the particular remodeling effect required, the control unitmay energize the electrodes with about 0.25 to 5 Watts average power for1 to 180 seconds, or with about 0.25 to 900 Joules. Higher energytreatments may be done at lower powers and longer durations, such as 0.5Watts for 90 seconds or 0.25 Watts for 180 seconds. In monopolarembodiments, the control unit may energize the electrodes with up to 30Watts for up to 5 minutes, depending on electrode configuration anddistance between the electrodes and the common ground. A shorterdistance may provide for lower energy for a shorter period of timebecause energy travels over more localized area with fewer conductivelosses. In an example embodiment for use in renal denervation, energy isdelivered for about 30 seconds at a treatment setting of about 5 Watts,such that treatment zones are heated to about 68° C. during treatment.As stated above, power requirements may depend heavily on electrode typeand configuration. Generally, with wider electrode spacing, more poweris required, in which case the average power could be higher than 5

Watts, and the total energy could exceed 45 Joules. Likewise, using ashorter or smaller electrode pair would require scaling the averagepower down, and the total energy could be less than 4 Joules. The powerand duration may be, in some instances, calibrated to be less thanenough to cause severe damage, and particularly less than enough toablate diseased tissue within a blood vessel. The mechanisms of ablatingatherosclerotic material within a blood vessel have been well described,including by Slager et al. in an article entitled, “Vaporization ofAtherosclerotic Plaque by Spark Erosion” in J. of Amer. Cardiol. (June,1985), on pp. 1382-6; and by Stephen M. Fry in “Thermal and DisruptiveAngioplasty: a Physician's Guide”; Strategic Business Development, Inc.,(1990), the full disclosure of which is incorporated herein byreference.

In some embodiments, energy treatments applied to one or both of thepatient's renal arteries may be applied at higher levels than would bepossible in other passageways of the body without deleterious effects.For instance, peripheral and coronary arteries of the body may besusceptible to a deleterious long-term occlusive response if subjectedto heating above a certain thermal response limit. It has beendiscovered that renal arteries, however, can be subjected to heatingabove such a thermal response limit without deleterious effect.

In some embodiments, energy treatments may be applied to one or both ofthe patient's renal arteries to affect sympathetic nerve activity in thekidneys in order to moderate both systolic and diastolic forms of CHF.The application of therapeutic thermal energy to the tissues proximatethe renal artery may be effective in reducing the sympathetic nerveactivity so as to mitigate the biological processes and the resultingeffects of CHF. In some embodiments, a mild application of a controlleddose of thermal energy in a rapid procedure (e.g. 10 minutes or less oftherapy time per kidney) is used so as to provide a simple procedure forthe clinical staff while providing a procedure that minimizes the painfelt by a patient while maximizing the efficacy of the procedure. Theballoon-mounted electrodes and energy delivery methods of the presentdisclosure may be particularly well suited for the application of energyto reduce sympathetic nerve activity related to chronic hypertension, inconjunction with or separate from, systolic and diastolic CHF.

In some embodiments, the electrode pads described herein may beenergized to assess and then selectively treat targeted tissue toachieve a desired therapeutic result by a remodeling of the treatedtissue. For example, tissue signature may be used to identify tissuetreatment regions with the use of impedance measurements. Impedancemeasurements utilizing circumferentially spaced electrodes within a bodypassage may be used to analyze tissue. Impedance measurements betweenpairs of adjacent electrodes may differ when the current path passesthrough diseased tissue, and when it passes through healthy tissues of aluminal wall for example. Hence, impedance measurements between theelectrodes on either side of diseased tissue may indicate a lesion orother type of targeted tissue, while measurements between other pairs ofadjacent electrodes may indicate healthy tissue. Other characterization,such as intravascular ultrasound, optical coherence tomography, or thelike, may be used to identify regions to be treated either inconjunction with, or as an alternate to, impedance measurements. In someinstances, it may be desirable to obtain baseline measurements of thetissues to be treated to help differentiate adjacent tissues, as thetissue signatures and/or signature profiles may differ from person toperson. Additionally, the tissue signatures and/or signature profilecurves may be normalized to facilitate identification of the relevantslopes, offsets, and the like between different tissues. Impedancemeasurements can be achieved at one or more frequencies, ideally twodifferent frequencies (low and high). Low frequency measurement can bedone in range of about 1-10 kHz, or about 4-5 kHz and high frequencymeasurement can be done in range of about 300 kHz-1 MHz, or betweenabout 750 kHz-1 MHz. Lower frequency measurement mainly represents theresistive component of impedance and correlates closely with tissuetemperature where higher frequency measurement represents the capacitivecomponent of impedance and correlates with destruction and changes incell composition.

Phase angle shift between the resistive and capacitive components ofimpedance also occurs due to peak changes between current and voltage asresult of capacitive and resistive changes of impedance. The phase angleshift can also be monitored as means of assessing tissue contact andlesion formation during RF denervation.

In some embodiments, remodeling of a body lumen can be performed bygentle heating in combination with gentle or standard dilation. Forexample, an angioplasty balloon catheter structure having electrodesdisposed thereon might apply electrical potentials to the vessel wallbefore, during, and/or after dilation, optionally in combination withdilation pressures which are at or significantly lower than standard,unheated angioplasty dilation pressures. Where balloon inflationpressures of 10-16 atmospheres may, for example, be appropriate forstandard angioplasty dilation of a particular lesion, modified dilationtreatments combined with appropriate electrical potentials (throughflexible circuit electrodes on the balloon, electrodes depositeddirectly on the balloon structure, or the like) described herein mayemploy from 10-16 atmospheres or may be effected with pressures of 6atmospheres or less, and possibly as low as 1 to 2 atmospheres. Suchmoderate dilation pressures may (or may not) be combined with one ormore aspects of the tissue characterization, tuned energy, eccentrictreatments, and other treatment aspects described herein for treatmentof body lumens, the circulatory system, and diseases of the peripheralvasculature.

In many embodiments, gentle heating energy added before, during, and/orafter dilation of a body lumen may increase dilation effectiveness whilelowering complications. In some embodiments, such controlled heatingwith a balloon may exhibit a reduction in recoil, providing at leastsome of the benefits of a stent-like expansion without the disadvantagesof an implant. Benefits of the heating may be enhanced (and/orcomplications inhibited) by limiting heating of the adventitial layerbelow a deleterious response threshold. In many cases, such heating ofthe intima and/or media may be provided using heating times of less thanabout 10 seconds, often being less than 3 (or even 2) seconds. In othercases, very low power may be used for longer durations. Efficientcoupling of the energy to the target tissue by matching the drivingpotential of the circuit to the target tissue phase angle may enhancedesirable heating efficiency, effectively maximizing the area under theelectrical power curve. The matching of the phase angle need not beabsolute, and while complete phase matching to a characterized targettissue may have benefits, alternative systems may pre-set appropriatepotentials to substantially match typical target tissues; though theactual phase angles may not be matched precisely, heating localizationwithin the target tissues may be significantly better than using astandard power form.

In some embodiments, monopolar (unipolar) RF energy application can bedelivered between any of the electrodes on the balloon and returnelectrode positioned on the outside skin or on the device itself, asdiscussed above. Monoploar RF may be desirable in areas where deeplesions are required. For example, in a monolpolar application, eachelectrode pair may be powered with positive polarity rather than havingone positive pole and one negative pole per pair. In some embodiments, acombination of monopolar and bipolar RF energy application can be donewhere lesions of various depth/size can be selectively achieved byvarying the polarity of the electrodes of the pair.

c. Target Temperature

The application of RF energy can be controlled so as to limit atemperature of target and/or collateral tissues, for example, limitingthe heating of target tissue such that neither the target tissue nor thecollateral tissue sustains irreversible thermal damage. In someembodiments, the surface temperature range is from about 50° C. to about90° C. For gentle heating, the surface temperature may range from about50° C. to about 70° C., while for more aggressive heating, the surfacetemperature may range from about 70° C. to about 90° C. Limiting heatingso as to inhibit heating of collateral tissues to less than a surfacetemperature in a range from about 50° C. to about 70° C., such that thebulk tissue temperature remains mostly below 50° C. to 55° C., mayinhibit an immune response that might otherwise lead to stenosis,thermal damage, or the like. Relatively mild surface temperaturesbetween 50° C. and 70° C. may be sufficient to denature and breakprotein bonds during treatment, immediately after treatment, and/or morethan one hour, more than one day, more than one week, or even more thanone month after the treatment through a healing response of the tissueto the treatment so as to provide a bigger vessel lumen and improvedblood flow.

In some embodiments, the target temperature may vary during thetreatment, and may be, for instance, a function of treatment time. FIG.7 illustrates one possible target temperature profile for a treatmentwith a duration of 30 seconds and a twelve second ramp up from nominalbody temperature to a maximum target temperature of about 68° C. In theembodiment shown in FIG. 7, the target temperature profile during thetwelve second ramp up phase is defined by a quadratic equation in whichtarget temperature (T) is a function of time (t). The coefficients ofthe equation are set such that the ramp from nominal body temperature to68° C. follows a path analogous to the trajectory of a projectilereaching the maximum height of its arc of travel under the influence ofgravity. In other words, the ramp may be set such that there is aconstant deceleration in the ramp of temperature (d²T/dt²) and alinearly decreasing slope (dT/dt) in the temperature increase as 12seconds and 68° C. are reached. Such a profile, with its gradualdecrease in slope as it approaches 68° C., may facilitate minimizingover and/or undershoot of the set target temperature for the remainderof the treatment. In some embodiments, the target temperature profile ofFIG. 7 will be equally suitable for bipolar or monopolar treatments,although, in at least some monopolar embodiments, treatment time may beincreased.

FIGS. 8, 9, and 10 illustrate additional target temperature profiles foruse in various embodiments of the disclosure. FIG. 8 illustratesprofiles with varying rise times and set target temperatures (e.g. oneprofile with an approximately 3 second rise time and 55° C. settemperature, one with a 5 second rise time and 60° C. set temperature,one with an 8 second rise and 65° C. set temperature, one with a 12second rise and 70° C. set temperature, and one with a 17 second riseand 75° C. set temperature).

FIGS. 9 and 10 illustrate temperature profiles that utilize differentrise profiles, some of which approach the set target temperaturerelatively aggressively (e.g., the “fast rise” profiles), others ofwhich approach the set target temperature less aggressively (e.g., the“slow rise” profile). It has been experimentally determined that the“medium enhanced rise” temperature profile shown in FIG. 10 providesoptimal results for at least some treatment protocols, although not allembodiments of the present disclosure are limited to this temperatureprofile, and different treatments and different circumstances mayadvantageously use other profiles. The medium enhanced rise may be anexample embodiment in that it efficiently warms target tissue to thetarget temperature while avoiding the deleterious microscopic thermaldamage that a more aggressive heating profile may cause while alsoproviding for an optimized overall treatment time. For each of thetarget temperature profiles shown, a temperature ramp embodying orapproximating a quadratic equation may be utilized, however, anyfunction or other profile that efficiently heats tissue, optimizestreatment time, and avoids thermal damage to target tissue may be used.However, in still other embodiments, it will not be necessary to utilizea temperature profile that achieves all of these goals. For instance andwithout limitation, in at least some embodiments, optimization oftreatment time may not be essential.

Both bench top and animal experimentation were undertaken to optimizeand verify the target temperature profile used in denervationembodiments of the Vessix system. The following summarizes the bench topexperimentation and analysis supporting the selection of the mediumenhanced rise temperature profile as an example embodiment.

The tests were carried out to determine which rise time algorithm wouldprovide optimal levels of effectiveness and safety. Some previous risetime algorithms had simply gone up to the set temperature as fast aspossible, and it was believed that this was not necessarily the bestcourse of action in at least some circumstances. Efficacy wasqualitatively assessed with three dimensionless parameters. Theobjective was to determine the algorithm that would produce the leastamount of charring, denaturing, and dehydrating of the tissue at thetreatment zone, based on visual inspection, while also providing goodefficacy.

A water bath was brought up to 37° C. to simulate body temperature, anda liver sample was placed in the bath to simulate conditions in vivo.Good apposition of the device was verified by noting the impedancevalues of the electrode-tissue interface of each bipolar electrode pairin contact with tissue. A higher impedance (>500 Ohms) was used as thebenchmark for good apposition.

After the temperature profiles of FIGS. 9 and 10 were run, the liverspecimen was measured at each treatment site for the length and width ofthe lesion at the surface, the depth of penetration, and length andwidth of the lesion at a 2 mm depth. The analyst had no knowledge ofwhich treatments had been done in which order so as to reduce reportingbias. Any observations of significant tissue damage were also recorded.

FIGS. 11 and 12 show in tabular form efficacy metrics that were createdto relate depth of penetration to other efficacy measures. The first isdepth of penetration divided by the square root of the area of thelesion at the surface. This metric relates the depth to the lesiondamage on the surface to the area of the surface lesion in anon-dimensional form. A value of 100% means that the depth ofpenetration was equal to the average size of the surface lesion. Thenext metric is area at 2 mm divided by the area at the surface. Thismetric reveals how well the heat is penetrating the tissue. A value of100% means that the areas at 2 mm deep and surface area are the same.The last metric is depth of penetration times the width of the lesion at2 mm divided by the area at the surface. This number providesinformation about the general shape of the lesion, and whether theenergy tends to propagate radially from the electrode or pierce thetissue. A value of 100% means that the cross sectional area of lesionsize was equal to the size of the surface of the lesion.

After carefully reviewing all of the experimental data, it was decidedthat the medium enhanced rise profile was the best temperature risealgorithm to use for certain embodiments, although, again, other targettemperature profiles may also be appropriately used in conjunction withthe disclosed embodiments of the present disclosure.

d. Control Algorithm

FIGS. 13 and 14 illustrate one embodiment of a method for controllingenergy application of an electrosurgical device, such as those describedabove and shown in FIGS. 1-6, or other devices, based on a targettemperature profile, such as those described above and shown in FIGS.7-10, or other profiles. The control method may be executed using theprocessing functionality of the control unit 110 of FIG. 1 and/orcontrol software, described in further detail above, or in othermanners. In at least some instances, the control method provides forfine regulation of temperature or other treatment parameter(s) at thevarious treatment sites of the device, while utilizing a relativelysimple and robust energy generator to simultaneously energize several ofthe electrodes or other delivery sites at a single output setting (e.g.voltage), which may minimize cost, size and complexity of the system.The control method may minimize deviation from target temperature orother treatment parameter(s), and hence minimize variation in demand onthe energy generator (e.g. voltage demand) during any time slice of thetreatment.

In some embodiments, it will be desirable to regulate the application ofRF or other energy based on target temperature profiles such as thosedescribed above to provide for a gentle, controlled, heating that avoidsapplication of high instantaneous power and, at a microscopic level,associated tissue searing or other damage, which could undesirablyresult in heat block or otherwise cause a net reduction in thermalconduction heat transfer at the device/tissue interface. In other words,by avoiding higher swings in temperature and the resultant heavierinstantaneous application of energy to reestablish temperature near thetarget temperature, tissue integrity at the immediate interface locationmay be preserved. Tissue desiccation may result in a net loss of thermalconductivity, resulting in reduced effective transfer of gentle,therapeutic delivery of energy to target tissues beyond theelectrode/tissue interface.

Those of skill in the art will appreciate that although the particularcontrol method of FIGS. 13 and 14 is presented for purposes ofillustration in the context of the particular electrosurgical devicesalready described above, that these control methods and similar methodscould be beneficially applied to other electro-surgical devices.

In general, the control method embodiment of FIGS. 13 and 14 seeks tomaintain the various treatment sites at a pre-defined targettemperature, such as at one of the target temperature profiles of FIGS.7-10. It does so in this embodiment primarily by regulating outputvoltage of the RF generator and determining which of the electrodes willby energized at a given time slice (e.g. by switching particularelectrodes on or off for that cycle).

The output setting of the generator and switching of the electrodes maybe determined by a feedback loop that takes into account measuredtemperature as well as previous desired output settings. During aparticular treatment cycle (e.g. a 25 millisecond slice of thetreatment), each of the electrodes may be identified for one of threestates: off, energized, or measuring. In some embodiments, electrodeswill only be in energized and/or measuring states (an electrode that isenergized may also be measuring) if they meet certain criteria, with thedefault electrode state being off. Electrodes that have been identifiedas energized or measuring electrodes may have voltage applied or bedetecting temperature signals for a portion of the cycle, or for theentire cycle.

The control loop embodiment of FIGS. 13 and 14 is designed to keep asmany candidate electrodes as possible as close to target temperature aspossible while minimizing variations in temperature and hence minimizingvariations in voltage demand from treatment cycle to treatment cycle.FIG. 15 shows an exemplar time/temperature plot over four treatmentcycles for an electrode illustrating how one embodiment of a controlalgorithm maintains the target temperature.

The control loop embodiment of FIGS. 13 and 14 will now be described indetail.

As indicated at step 1300, each electrode is initially set to off. Atstep 1302, one of the electrodes is designated as a primary electrodefor that treatment cycle. As discussed in further detail below, duringthe treatment, the primary electrode designated will vary from treatmentcycle to treatment cycle (e.g. cycle through all of the availableelectrodes). The determination of which electrode will be designated asthe primary electrode may be done by accessing a look-up table or usingany other suitable functionality for identifying a primary electrode andvarying the choice of primary electrode from treatment cycle totreatment cycle.

At step 1302, additional electrodes may also be designated as candidateelectrodes for energization and/or measuring during that treatmentcycle. The additional electrodes designated may be candidates by virtueof being in a certain relationship or lacking a certain relationshiprelative to the designated primary electrode for that treatment cycle.

For instance, in some bipolar electrode embodiments, some of theelectrodes on the electro-surgical device may be arranged in a mannersuch that there may be a potential for current leakage between theprimary electrode and those other electrodes if both the primaryelectrode and those additional electrodes are energized simultaneouslyin a treatment cycle, which may undesirably cause interference with thetemperature measurement by the associated heat sensing device,imprecision in the amount of energy delivered at each electrode, orother undesirable consequences. For instance, in the embodimentillustrated in FIG. 1C, if electrode pad 150 c is designated as aprimary electrode, electrode pads 150 d and 170 d, which have negativepoles immediately adjacent or proximate the positive pole of electrodepad 150 c, may be considered to be not candidates for measuring and/orenergization for that particular treatment cycle, since they areleakage-inducingly proximate to the designated primary electrode.Additionally, in this embodiment, electrode pad 150 b, which has apositive pole immediately adjacent or proximate the negative pole ofelectrode pad 150 c, may be considered to not be a candidate, since itis also leakage-inducingly proximate to the designated primaryelectrode. Furthermore, in this particular embodiment, electrode pad 170b would also be considered a non-candidate because it is on the sameflex structure as the leakage-inducingly proximate electrode pad 150 b.Finally, in this particular embodiment, electrode pads 150 a and 170 awould be considered candidates because they are adjacent non-candidates.

As another non-limiting example, in some monopolar electrodeembodiments, the candidate electrodes are the monopolar electrodes thathave similar measured or estimated electrical circuit properties to oneor more measured or estimated properties of the electrical circuitassociated with the primary electrode. In other words, in some monopolarsystems, it may be desirable to only simultaneously energize monopolarelectrodes that define substantially similar electrical circuits to theelectrical circuit defined by the primary monopolar electrode (e.g. thecircuit defined by the monopolar electrode, the common electrode, and apathway through the patient's tissue). In some instances, this mayfacilitate uniformity in current flow during energization. In otherembodiments, a pre-defined table or other listing or association willdetermine which electrodes are candidate electrodes based on the currentprimary electrode.

In at least some embodiments, switches associated with non-candidateswill be opened to isolate the non-candidates from the rest of thesystem's circuitry. This switching, in at least some embodiments, couldalso or alternatively be used to otherwise maximize the number ofavailable electrode pairs available for energization provided that acommon ground between pairs is not affected by the switching off.

In other embodiments, the electro-surgical device may be configured toavoid the potential for leakage or otherwise take such leakage intoaccount, and, accordingly, all the electrodes of the device may becandidates for energization and/or measuring during a treatment cycle.

In some embodiments, the assignment of an electrode as either theprimary electrode, candidate, or non-candidate may be determined by asequence matrix or look up table in an array that identifies the statusof each of the electrodes and an order for the designation of primaryelectrodes. In one non-limiting embodiment, the primary electrodedesignation cycles circumferentially through the proximate electrodesand then circumferentially through the distal electrodes (e.g. in FIG.1C, the sequence may be 170 a, b, c, d, 150 a, b, c, d). However, anypattern or other methodology could be used including ones that optimizedistance between the next in sequence, the nearness of next in sequence,or the evenness of distribution.

In some embodiments, additional conditions may result in a particularelectrode being set to off for a particular treatment cycle and/or forthe remainder of the treatment. For instance, as discussed below, duringthe course of treatment, as much as 4° C. temperature overshoot may beallowed (e.g., even if such overshoot results in the electrode not beingenergized, it will not necessarily be set to off and still available formeasuring); however, in at least some embodiments, if eight consecutivetreatment cycles measure temperature overshoot for a particularelectrode, that electrode will be set to off for the remainder of thetreatment, with the treatment otherwise continuing and without otherwisechanging the control loop process discussed below.

At step 1304, target voltages for each of the primary and othercandidate electrodes are determined. In this particular embodiment, atarget voltage for a particular electrode may be determined based on atemperature error associated with the treatment site of that electrodeas well as the last target voltage calculated (although not necessarilyapplied) for that electrode. Temperature error may be calculated bymeasuring the current temperature at the treatment site (e.g. utilizingthe heat sensing device associated with the electrode proximate thattreatment site) and determining the difference between the measuredtemperature and the target temperature for that instant of time in thetreatment.

Those of skill in the art will appreciate that while this particularembodiment is described as using voltage as a control variable, thatpower could be used as an alternative to voltage for the controlvariable, based on, for instance, a known relationship between power andvoltage (i.e. power equaling voltage times current or impedance).

FIG. 14 illustrates one embodiment of a sub-routine for determining atarget voltage for an electrode. At 1402, a temperature error fromtarget (T_(e)) is calculated by subtracting the target temperature atthat time (T_(g)) from the actual temperature (T) (e.g. as measured by athermistor associated with that electrode). At 1404, it is determinedwhether the temperature error calculated at 1402 is greater than 4° C.(i.e. if the target temperature is 68° C., determining if thetemperature as measured by the thermistor is above 72° C.). If thetemperature error is greater than 4° C., the sub-routine assigns thatelectrode a target voltage of zero for that treatment cycle at 1406. Ifthe temperature error is not greater than 4° C., the subroutine proceedsto 1408 and determines whether the temperature error is greater than 2°C. If the temperature error is greater than 2° C., at 1410, thesub-routine assigns that electrode a target voltage of 75% (or anotherpercentage) of the last assigned target voltage for that electrode. Ifthe temperature error is not greater than 2° C., at 1412, thesub-routine may assign a target voltage for that electrode based on theequation:

V=K _(L) V _(L) +K _(P) T _(e) +K _(I)∫^(t) _(t-n sec) T _(e AVE)

-   -   where:        -   V is the target voltage;        -   T_(e) is a temperature error from target;        -   V_(L) is the last assigned electrode voltage;        -   K_(L), K_(P), and K_(I) are constants; and        -   n is a time value ranging from 0 to t seconds.

In some embodiments, including the embodiment of FIG. 14, the equationused may be:

V = 0.75  V_(L) + K_(p)T_(e) + K_(I)∫_(t − 1  sec )^(t)T_(e A V E)

-   -   where:        -   V is the target voltage;        -   T_(e) is the temperature error from target;        -   V_(L) is the last assigned electrode voltage;        -   K_(P) is a constant from proportionate control; and        -   K_(I) is a constant from integral control.

In some embodiments, it may be beneficial to use only the last assignedelectrode voltage for determining a target voltage, rather thanutilizing averages of voltages or voltages from earlier treatmentcycles, as, in some cases, use of earlier voltages may be a source forcomputational error in embodiments that focus on fine control of thetarget temperature.

Returning to FIG. 13, once target voltages are determined for theprimary electrode and other candidate electrodes, at step 1306, it isdetermined whether the target voltage for the primary electrode isgreater than zero. If not, at 1308, the output voltage of the RFgenerator is set for that treatment cycle to the lowest target voltagedetermined at 1304 for the other candidate electrodes. If the targetvoltage determined at 1304 for the primary electrode is greater thanzero, at 1310, the output voltage of the RF generator is set for thattreatment cycle to the target voltage of the primary electrode.

At step 1312, the primary and other candidate electrodes with a targetvoltage greater than zero are identified as electrodes to be energized.In alternative embodiments, candidate electrodes other than the primarywill only be energized if the target voltages determined for thoseelectrodes is 6V greater than the set voltage.

In still other embodiments, candidate electrodes other than the primarywill only be energized if the target voltages determined for theseelectrodes are 1, 5 or 10V greater than the set voltage.

At step 1314, it is determined whether the electrodes to be energizedare currently at temperatures greater than 68° C. Those electrodes thatare at temperatures greater than 68° C. are switched off or otherwiseprevented from being energized in that treatment cycle, and thoseelectrodes otherwise meeting the above criteria are energized at the setvoltage at step 1316. Subsequently, another treatment cycle begins, andthe control loop of FIG. 13 is repeated until the treatment is complete.In some embodiments, each treatment cycle will be non-overlapping withthe previous and next cycles (e.g. the steps of FIG. 13 will becompletely performed before the next cycle's steps begin), although, inother embodiments, the cycles may be overlapping at least to someextent.

FIGS. 16-23 are charts of temperature (target and actual) and targetvoltage over time for a treatment employing a Vessix System for renaldenervation that utilizes the control loop of FIG. 13 to regulate actualtemperature at the device's eight electrodes to the target temperatureprofile. It should be understood that the target voltage charted inthese Figures is not the same as the actual voltage applied to theelectrodes, since, as described above, the target voltage for only oneof the electrodes is used to set the actual voltage applied in eachtreatment cycle. As shown in FIGS. 16-23, the control loop of FIG. 13functions to precisely maintain the actual temperature at each electrodeof the device at the target temperature. As also shown in FIGS. 16-23,measured impedance may decrease in some instances over the course of thetreatment (particularly at the beginning of the treatment), reflectingincreased mobility of the ions in the tissue in response to the highfrequency RF energy.

It has been experimentally determined that an example embodiment of thetemperature control method described above, when employed as part of theVessix System for Renal Denervation, provides effective reduction ofnorepinephrine (NEPI) concentration. In one experiment, efficacy andsafety of the Vessix System for Renal Denervation was assessed inhealthy juvenile Yorkshire swine at 7 and 28 days post-treatment,including an assessment of kidney NEPI concentration levels at 7 dayspost-treatment. FIG. 25 is a table summarizing the study design for thisparticular experiment. Efficacy of groups 1 and 2 was measured aspercent reduction of NEPI level in the treated arteries vs. untreatedcontralateral control kidney in each animal at 7 days. FIG. 26 showspercent NEPI reduction of both groups (as means+/−SD). There were nosignificant changes in body weight, body condition score or clinicalpathology parameters in any animal over the course of the study.Overall, the average baseline vessel diameters were similar amongstgroups across all time points. Luminal gain or loss was calculated(average pre-necropsy−average baseline diameter) and exhibited similarluminal gains for treated vessels when compared to vessels of theanimals that were not treated. Representative angiography images of therenal artery pre-treatment, 7 and 28 days post RF treatment are shown inFIGS. 27-30. No perforation, dissection, thrombus nor emboli weredetected acutely or chronically via angiography analysis.

e. Nerve Signal Stimulation and Monitoring

In at least some of the embodiments described above, or in alternativeembodiments, renal-denervation treatment methods and systems may providefor stimulation of nerve signals and monitoring for nerve signalresponse in the tissue proximate the treated renal artery. In someinstances, this electrogram of neural activity may provide an assessmentof the denervation treatment's efficacy and/or provide feedback forregulating the treatment. In at least some embodiments, such anelectrogram provides for an assessment of whether neural activity ispresent and/or has shifted (e.g. decreased) relative to a measuredbaseline, and does not involve mapping or quantifying the presence ofneural tissue proximate the renal artery.

In one embodiment, the same electrode assemblies used to deliver thedenervation treatment, such as the bi-polar electrode pairs on thedistal and proximal electrode pads 150 a-d and 170 a-d shown in FIG. 1C,may also be configured for stimulation of nerve signals and monitoringfor nerve signal responses. For instance, one of the proximal bipolarelectrode pairs on one of proximal electrode pads 150 a-d may be used tostimulate a nerve signal and one of the distal bipolar electrode pairson one of distal electrode pads 170 a-d may be used to monitor for anerve signal response. Alternatively, a distal bipolar electrode may beused for stimulation and a proximal bipolar electrode may be used formonitoring. In these or other embodiments, stimulation and sensing maybe performed by axially or circumferentially adjacent electrode pairs.

Electrodes 222 having the size, spacing, other geometries and othercharacteristics as described above in the context of FIG. 2A may besufficient for stimulation and monitoring of nerve signals, although, inalternative embodiments, the electrodes may be further reduced in sizeand/or other characteristics may modified to provide higher signalresolution. Other modifications to the systems and devices describedherein may also be made to minimize interference with the stimulationand (particularly) monitoring of nerve signals. For instance, in someembodiments, the layout of the system's circuitry (such as the RFgenerator's internal circuitry) and/or the pairing, twisting, and othercharacteristics of the wiring associated with the catheter/flexcircuitry may be optimized to reduce the inherent capacitance of thecircuitry to provide for reduced electromagnetic flux.

In alternative embodiments, the electrodes used to stimulate and/ormonitor for nerve signals may be different from the electrodes used todeliver the energy treatment. The stimulation/monitoring electrodes mayhave positions, geometries, and other characteristics optimized forstimulation/monitoring and the energy delivery electrodes may havepositions, geometries and other characteristics optimized for deliveringthe energy treatment. FIG. 42 shows an example of a catheter includingelectrodes for delivering an energy treatment (similar to the electrodesshown in FIG. 10) and separate electrodes (in the form, here, ofcircumferential ring electrodes on distal and proximal ends of theexpandable device) for stimulating and monitoring for nerve signals.FIG. 43 shows an example of a catheter including separate proximal anddistal expandable devices carrying ring electrodes for stimulating andmonitoring for nerve signals. The electrodes of FIGS. 42 and 43 may eachbe a bipolar electrode, a monopolar electrode, or may constitute abipolar electrode between the proximal and distal electrode rings. Asshown in FIG. 24D the schematic representation of electrodes may beshown on a user interface to identify electrode regions that areavailable to be energized, and may further include indication ofsufficient tissue apposition by the measurement of impedance. Because auser interface may show electrode configurations in a schematic form, itshould be understood that the schematic image should not be limiting tothe types of electrode configurations present on the expandablestructure. Electrodes may be any one or more of rings, bipolar pairs,point electrodes, axially elongate electrodes, and the like.

In monopolar embodiments, the electrodes serve as the positive pole forstimulating and sensing during treatment, while a separate negative poleis used as a ground. The negative pole may be located on the expandablestructure, at one or more points on the catheter body, or external tothe patient in the form of a grounding pad. In monopolar configurations,signal processing and filtering (as further described below) aredesirable options because of the relatively large difference inmagnitudes between energy delivery and nerve response detection.

The RF generator and other circuitry of the control unit 110 shown anddescribed for FIG. 1A may be used to generate the nerve stimulationsignal and monitor for the response, although, in other embodiments, aseparate device may be associated with the system for generating nervestimulation and/or monitoring response.

In one embodiment, the nerve stimulation may be a voltage in the rangeof about 0.1V to about 5V, or about 0.5V, applied by the first electrodefor a period of about 1 second or less, or about 0.5 milliseconds,followed by a pulse width modulation, which may shock a nerve tissueinto propagating a nerve signal. The pulse signal may be of any formwith a square wave being one example form because the rapid on/offnature of the wave form efficiently stimulates a nerve response with noramp to or from peak voltage.

Neural activity may be assessed by measuring one or more of amplitude ofthe nerve signal in response to the stimulation, speed of the nervesignal in response to the stimulation, and/or fractionated amplitude ofthe nerve signal. Here, a fractionated amplitude refers to a netreduction and change to the nerve conduction signal as compared to apre-treatment baseline. A pre-treatment signal would be expected to havea relatively larger amplitude and smoother transition of slope while asignal from a nerve having received at least some treatment would beexpected to have a relatively lower amplitude and a less smooth, sudden,or broken transition in slope indicative of interrupted nerve conductiondue to treatment. These measurements can be determined by measuring achange in voltage at the second electrode and/or a measured time betweenthe stimulation and the response, and, in at least some embodiments, mayutilize high and/or low pass filtering to differentiate the nerve signalfrom background noise.

Currently, interventional energy delivery therapies such as renaldenervation are performed based on anatomical landmarks. In the exampleof renal denervation, it is known that a majority of nerves are locatedalong the length of renal arteries. Post treatment assessment is basedon secondary effects such as NEPI and blood pressure reductions, whichare not typically immediate indicators and are not indicative of nerveviability.

In the current state of the art there is no means available to directlyassess functional behavior of renal nerves in real-time during a renaldenervation procedure. A solution to this problem is the use ofalternating current or direct current to deliver sub-threshold or lowstimulation signals in the vicinity of renal nerves within renalarteries to access their activity pre and post renal denervationtreatment.

High resolution rapid nerve viability measurements may be accomplishedvia multiple localized electrodes such as those shown in FIGS. 1B and1C, however, it should be noted that embodiments are not limited tobipolar flex circuit electrodes on balloons. Any electrode configuration(monopolar or bipolar) suitable to be mounted to a catheter-basedexpandable structure may be employed; ring electrodes, linear or spiralelectrodes, point electrodes, and the like, may be mounted to baskets,balloons, or any other such type of structure used in catheter systems.

The measurement technique employs electric stimulation from at least oneelectrode over the path of a nerve to evoke the generation of an actionpotential that spreads along the excited nerve fibers. That actionpotential is then recorded on another point. This technique may be usedto determine the adequacy of the conduction of the nerve impulse as itcourses down a nerve, thereby detecting signs of nerve injury. Thedistance between electrodes and the time it takes for electricalimpulses to travel between electrodes are used to calculate the speed ofimpulse transmission (nerve conduction velocity). A decreased speed oftransmission indicates nerve damage.

Velocity, amplitude, as well as shape of the response followingelectrical stimulation of renal nerves will be measured via multipleelectrodes on the balloon catheter. Abnormal findings include conductionslowing, conduction blockage, lack of responses, and/or low amplituderesponses

Referring to FIGS. 44 and 45, electrical signal morphology is indicativeof a change in nerve conduction as evidenced by the change in the degreeof fractionation combined with slow conduction. FIG. 44 shows arepresentative nerve signal 4401 in the pre-treatment or baselinecondition. FIG. 45 shows a representative nerve signal 4501 after havingreceived at least some energy treatment. When comparing signal 4401 tosignal 4501, it is evident that the amplitude of the nerve signal hasbeen reduced while the pulse width has been increased. It is alsoevident that the slopes and changes in slopes of the signal 4501 aremuch less smooth than the slopes and changes in slopes of the signal4401. This is illustrative of how a nerve responds to the energytreatment of the subject disclosure; as energy is delivered the nerveconductive properties are reduced or eliminated thereby causing thenerve signals to be reduced, less continuous, and slower in velocity.

Nerve signal measurement may be optimized using signal filtering suchthat the influence of cardiac electrical signals, stimulation signals,and system noise are filtered out of the nerve sensing circuit so as tooptimize the accuracy and sensitivity of the circuit. Signal filteringmay be accomplished through means such as band-pass filters. Forexample, a low-pass filter in the range of about 1 Hz to about 500 Hz,with an example value of 100 Hz and a high-pass filter in the range ofabout 1 kHz to about 10 kHz, with an example value of 5 kHz may beemployed to establish the frequency band of signals to be sensed andmeasured by the circuit. Measurements are then used as feedback appliedto the energy control algorithm used to regulate the delivery oftherapeutic energy.

In a monopolar embodiment sensing is from a broader field of tissuebecause energy flows from the one or more positive poles of electrodesto the negative pole or poles of a common grounding path. Applying thisconcept to the embodiment of FIGS. 1B and 1C, an example polarity wouldbe to use an external patch (not shown) as the positive pole while theelectrode assemblies 140 a-d serve as the negative poles of a commongrounding circuit used for nerve signal measurement. In this seeminglybackward application of energy for the purposes of sensing, theelectrode assemblies 140 a-d are more proximate to the nerve tissue ofinterest and hence may provide improved sensing accuracy by serving asnegative poles for sensing. During the energy delivery mode oftreatment, the polarities of the external patch and electrode assemblies140 a-d may be switched such that the electrode assemblies 140 a-d arethe positive poles and the external patch is the negative pole forgrounding.

In a bipolar embodiment, sensing is from a localized field of tissuebecause the positive and negative poles of electrode assemblies 140 a-dare immediately adjacent, and hence, the tissue volume sensed is muchmore localized than in a monopolar configuration. The close proximity ofelectrode poles in a bipolar arrangement may be desirable because theproximity of poles allows for an inherently lower quantity of energydelivery to energize tissue and an inherently higher degree ofmeasurement resolution because of the smaller tissue volume betweenpoles. Additionally, the electrode assembly 140 a-d configurationsprovide a proximal/distal linear spacing that allows for the sensing andmeasuring the linear travel of a nerve signal along a path as has beendescribed herein.

Nerve signal stimulation and measurement may occur before, during,and/or after the energy treatment. In one embodiment, neural activity isassessed prior to treatment to establish a baseline level of neuralactivity and is then reassessed after the treatment to determine whethera threshold level of change in neural activity has resulted. Any one ormore of percentage reduction in nerve signal amplitude, degree offractionation of signal slope, increase in duration of nerve signalpulse, and increase in time between nerve signal pulses may be used tomeasure a tissue response indicating that denervation in the targettissue has occurred or is in the process of occurring. In other words,total disruption of nerve activity may be a delayed response to thedenervation treatment, although some decrease in nerve activity mayoccur during or just after the denervation treatment sufficient toindicate the effectiveness of the treatment. In alternative embodiments,an effective denervation may be characterized as one in which no nervesignal is detected in response to a pre-determined stimulation.

Nerve signal assessment may also or alternatively be conducted duringthe energy treatment. For instance, the control algorithm shown in FIG.13 may be modified to allow time scale measurements of stimulated nerveactivity (such measurements being on the order of any of milliseconds,microseconds, nanoseconds, picoseconds, etc.) prior to or after eachelectrode firing cycle. These intra-cycle measurements may be comparedto a pre-treatment baseline, to measurements from earlier cycles, or toother standards.

In some embodiments, regardless of whether the nerve activity assessmentis conducted pre and post treatment, periodically between each treatmentcycle, or periodically after a certain number of treatment cycles, datafrom the neural activity assessments may be used to establish or adjustparameters for the denervation treatment. For instance, in theembodiment illustrated by FIGS. 13 and 14, while the set voltage foreach cycle may be a function of previous voltage applied and measuredand averaged temperature errors, total time at the treatment temperaturemay be a function of measured neural activity, or a function ofdeviation of measured neural activity from an earlier measured orpre-set baseline. One or more of measured amplitude of the nerve signal,speed of the nerve signal, and/or fractionated amplitude may beaccounted for in such an algorithm. Thus, if a significant decrease inneural activity is measured early in the denervation treatment, thetotal treatment time may be shortened. Conversely, if the nerve signalassessments are not measuring a decrease in neural activity, the totaltreatment time may be lengthened. Of course, feedback from the nervesignal assessment(s) may be used to vary additional or alternativeparameters of the denervation treatment.

Measuring of nerve signals may be directly integrated into the energydelivery and control methods described herein. As candidate electrodesare selected and energized in accordance with the control algorithm, theadditional function of nerve signal measuring may be integrated into thecontrol algorithm such that the additional control factor of nerveresponse increases the precision with which energy is delivered and atherapeutic response is achieved while avoiding the delivery of excessenergy in order to preserve pre-treatment issue cellular state to themaximum degree possible. As shown in FIG. 13A, an additional controlloop step 1313 may be used to evaluate whether the nerve signalreduction threshold has been met. If the nerve signal reductionthreshold is not met, the control loop then advances to loop step 1314to determine whether a candidate electrode has reached a temperaturethreshold. If at loop step 1313 a nerve is determined to have reachedthe signal reduction threshold, then the electrode may be deselected asa candidate electrode to be energized.

Treatment of Small/Branched Vessels and Other Passageways

The systems and devices described herein may be advantageously used insituations where other energy-based treatment systems and devices wouldnot be suitable. For instance, embodiments of the systems and devicesdescribed herein may be used in vessels and other passageways that aretoo small for treatment using other catheter-based energy treatmentsystems. In some instances, the systems and devices described herein maybe used in renal arteries or other vessels having diameters of less than4 mm and/or lengths of less than 20 mm. Other factors, such as vesseltortuosity and proximity of the treatment site to regions that shouldnot receive treatment, may be contra-indications for or otherwise notsuitable for treatment using earlier devices but not for at least someembodiments of the presently described systems and devices.

FIGS. 1D and E show 4 and 5 mm balloons with three electrode assemblieseach. The particular geometries of these electrode assemblies and othercharacteristics described in preceding sections, however, facilitatetheir use on smaller diameter balloons, such as 1, 2 or 3 mm balloons orintermediate sizes thereof. In some instances (such as in some 1 mmembodiments), the balloon may not include a guidewire lumen. FIG. 46shows one embodiment of a balloon with the main body 4601 being made ofKapton® a flexible polyimide film available from DuPont™, with theshoulders 4602 being made of a standard balloon material. In someinstances, the Kapton® body of the balloon of FIG. 46 may be used toeliminate the need for a separate layer of the flexible circuitassemblies used on the balloon, such as to eliminate the base layer 202shown in FIG. 2B, thereby reducing the profile of the flexible circuitassembly.

Other features of the systems and devices described above may alsofacilitate their use in vessels that are relatively small. For instance,delivering an energy treatment to a small diameter vessel may requireparticularly fine control over the amount of energy delivered and/or thetemperature increase caused by the treatment. As such, the particularelectrode energy delivery geometries, control algorithms, and otherfeatures described above may make the present systems and devicesparticularly suitable in such situations.

FIG. 47 schematically shows a typical primary renal artery 4701branching from the aorta 4702 to the kidney 4703. An embodiment of thepresent disclosure is shown where the balloon and electrode assembly4704 of the catheter is expanded and positioned for treatment of tissue.An energy dose is applied and the balloon is subsequently deflated andremoved or repositioned.

FIG. 48 schematically shows a primary 4801 and an accessory renal artery4802 branching from the aorta 4803 with both extending to the kidney4804. Accessory arteries may range in size from about 1 mm in diameterto about 5 mm in diameter. The renal arteries of FIG. 48 should beunderstood to be a simple schematic representation of what may vary fromsubject-to-subject in vivo. For instance, the arteries may vary indiameter, length, tortuosity, location, and number. Furthermore, thesevariations may be with respect to each artery as well as with respect toeach subject. FIG. 48 shows a first balloon catheter A positioned fortreatment in a smaller accessory artery and a second balloon catheter Bpositioned for treatment in a larger primary renal artery.

In practice, it may be possible that catheter A and catheter B are onein the same if the two arteries are sufficiently close in diameter toallow for complete balloon expansion and contact with the tissue of thearterial lumens. It may be further possible that catheter A and catheterB may be repositioned along the length of the respective arteriesdepending on the treatable length of each artery. It may also be furtherpossible that the primary and accessory arteries may be treatedsimultaneously should a physician so desire.

To applicant's knowledge, prior to the present disclosure, the treatmentof accessory renal arteries has not been possible because oftechnological limitations caused by overheating of small arteries, spaceconstraints when operating in luminal areas with smaller cross sections,and the difficulty of navigating tortuous pathways. Because theembodiments of the present disclosure use expandable, catheter-basedstructures, flexible circuit electrodes on balloons, the limitations of“one size fits all” devices are obviated. Balloon and electrodeassemblies of the present disclosure are incrementally sized andarranged to facilitate the precisely controlled thermal energy dose foran incremental range of luminal diameters. In other words, the balloonand electrode assembly is incrementally sized and arranged for optimizedoperation in a correspondingly sized lumen. The number of electrodes ischosen to avoid overheating of tissues. The balloon-based expandablestructure is able to navigate to a location at a smaller, unexpandeddiameter with flexibility. The large surface contact of an expandedballoon allows for uniformity in tissue contact while avoiding thebending and/or tight space constraints of single point probes or othersuch similar designs.

Accessory renal arteries are present in 25-30% of human patients;however these patients have been excluded from previous renaldenervation studies. Within the REDUCE-HTN Clinical Study (the fullcontents of Vessix Vascular clinical study protocol CR012-020 beingincorporated herein by reference) a subset of four subjects underwentsuccessful treatment of primary and, at least, one accessory renalartery using the Vessix Renal Denervation System (Vessix Vascular, Inc.;Laguna Hills, Calif.) that includes a 0.014 inch over-the-wirepercutaneous balloon catheter with up to 8 radiopaque gold electrodesmounted on the balloon surface in a longitudinally and circumferentiallyoffset pattern. In an exemplary embodiment, a catheter is connected to aproprietary automated low-power RF bipolar generator that delivers atemperature-controlled therapeutic dose of RF energy at about 68° C. forabout 30 seconds. The mean baseline office-based blood pressure (OBP) ofthis cohort was 189/93 mmHg. In addition to an average of 10.5denervations of each main renal artery, this cohort was treated with anaverage of 8 denervations per accessory renal artery.

In this study, for the four subjects, no peri-procedural complicationswere reported and immediate post-procedure angiography indicated norenal artery spasm or any other deleterious effects. These four subjectsdemonstrated improvement at two weeks post-procedure with a meanreduction in OBP of −32/−16 mmHg (190/97 to 167/91; 175/92 to 129/70;192/94 to 179/91; 183/87 to 138/55).

FIGS. 49 and 50 schematically illustrate non-limiting examples of renaldenervation treatments where energy delivery is selectively deliveredusing a subset of the electrodes of an electrode assembly. FIG. 49schematically illustrates a renal artery 4901 that includes a branch4902. In this instance, the balloon and electrode assembly 4903 ispositioned in the renal artery such that one of the electrodes 4904 isproximate an ostium joining the branch to the renal artery, and thus isnot in apposition with a vessel wall. As described above in someembodiments, systems and methods in accordance with the presentdisclosure may be configured to selectively energize the electrodes or asubset of electrodes in apposition with the vessel wall (e.g. electrodes4905 and 4906 in FIG. 49) while not energizing the electrodes or asubset of electrodes that are not in apposition with a vessel wall (e.g.electrode 4904). Those of skill in the art will appreciate that, inaddition to the example of FIG. 49, a variety of other factors couldresult in less than complete apposition between the electrode assemblyand vessel wall, including, without limitation, vessel tortuosity,changes in vessel diameter, presence or absence of buildup on the vesselwall, etc.

FIGS. 50A and B schematically illustrate a non-limiting example of arenal denervation treatment where an energy treatment is performed withthe electrode assembly and balloon at two positions in a renal artery5001. In FIG. 50A, the balloon is positioned such that all of theelectrodes 5002-5005 are in the renal artery 5001 and are potentialcandidates for energization. In FIG. 50B, after an energy treatment hasbeen performed at the position shown in FIG. 50A, the balloon andelectrode assembly has been withdrawn such that a portion of it remainsin the renal artery 5001 and a portion of it is in the aorta 5006. Inthe positioning shown in FIG. 50B, certain embodiments of systems andmethods of the present disclosure will be configured to select onlyelectrodes 5002 and 5005 (and any other electrodes positioned withinrenal artery 5001 and/or in apposition with a wall of the renal artery5001) as potential candidates for energization, with electrodes in theaorta 5006 identified as non-candidates for energization. As illustratedby FIGS. 50A and B, certain embodiments of the present disclosure mayfacilitate delivering energy to tissues at or proximate the ostiumjoining the aorta 5006 to the renal artery 5001, which may, in at leastsome patients, be an area of relatively high concentration of nervetissues.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of skill in theart will recognize that a variety of modifications, adaptations, andchanges may be employed.

What is claimed is:
 1. A renal-denervation treatment method, comprising:(a) delivering an RF energy treatment to a tissue proximate a renalartery using a catheter assembly of a renal denervation catheter system,wherein the denervation system includes an RF energy generator coupledwith the catheter assembly by a controller; (b) applying neural activitystimulation to the tissue proximate the renal artery using the catheterassembly; (c) assessing stimulated neural activity response of thetissue using the catheter assembly; and (d) determining a parameter ofthe RF energy treatment based on the assessed neural activity.
 2. Themethod of claim 1, further comprising outputting data relating to theassessed neural activity.
 3. The method of claim 2, wherein outputtingdata comprises outputting whether a sufficient decrease in neuralactivity has occurred.
 4. The method of claim 1, wherein assessing theneural activity comprises taking at least a first neural activitymeasurement and a second neural activity measurement.
 5. The method ofclaim 4, wherein taking the first neural activity measurement comprisestaking the first neural activity measurement before beginning thedelivery of the RF energy treatment to establish a base line neuralactivity measurement; wherein taking the second neural activitymeasurement comprises taking the second neural activity measurementafter beginning the delivery of the RF energy treatment; and wherein themethod further comprises determining whether neural activity has changedfrom the base line.
 6. The method of claim 5, wherein determiningwhether neural activity has changed from the base line comprisesdetermining whether the change in neural activity is at, above or belowa threshold.
 7. The method of claim 6, further comprising terminatingthe RF energy treatment once the change in neural activity is at orabove the threshold.
 8. The method of claim 1, wherein assessingstimulated neural activity response comprises periodically measuring forstimulated neural activity response during the RF energy treatment. 9.The method of claim 1, wherein applying neural activity stimulationcomprises energizing at least one electrode of the catheter assembly;and wherein assessing stimulated neural activity response comprisesusing a second electrode of the catheter assembly to monitor for thenerve response signal.
 10. The method of claim 9, wherein delivering theRF energy treatment comprises using the at least one electrode and thesecond electrode to deliver RF energy to the tissue.
 11. The method ofclaim 9, wherein monitoring for the nerve response signal comprises atleast one of measuring an amplitude of the nerve response signal,measuring a time delay between the nerve stimulation signal and thenerve response signal, and measuring a fractionated amplitude of thenerve response signal.
 12. The method of claim 9, further comprisingmeasuring at least one of an amplitude of the nerve response signal, apulse width of the nerve response signal, a slope or change in slope ofthe nerve response signal, a velocity of the nerve response signal, or atime delay of the nerve response signal.
 13. The method of claim 12,further comprising comparing the measurement to a base line measurementof an earlier nerve response signal.
 14. The method of claim 1, whereindetermining the at least one parameter of the RF energy treatmentcomprises adjusting the at least one parameter based on the assessedneural activity.
 15. The method of claim 14, wherein adjusting the atleast one parameter comprises adjusting a temperature profile of the RFenergy treatment.
 16. The method of claim 15, wherein adjusting the atleast one parameter comprises adjusting a length of time at a targettemperature of the target temperature profile.
 17. A renal-denervationmethod, comprising: (a) applying a first neural activity stimulation toa tissue proximate a catheter assembly of a renal denervation system;(b) measuring a first stimulated neural activity response of the tissueusing the catheter assembly; and (c) delivering an energy treatment tothe tissue proximate the renal artery using the catheter assembly; (d)measuring a second neural activity response of the neural tissue usingthe catheter assembly; and (e) determining a parameter of the energytreatment by comparing the first and second measured neural activities.18. A renal-denervation treatment system, comprising: (a) an elongatecatheter including an expandable structure at or near a distal end ofthe catheter, the expandable structure including a plurality ofelectrodes; (b) a power source electrically coupled to the plurality ofelectrodes; and (c) a processor configured to (1) energize at least asubset of the electrodes at a renal-denervation energy level; (2)energize one or more of the electrodes at a neural activity stimulationlevel; and (3) monitor for, using one or more of the electrodes, aneural activity response.
 19. The system of claim 18, wherein the neuralactivity stimulation level is a voltage in the range of about 0.1 V toabout 5 V applied for about 1 second or less.
 20. The method of claim19, wherein the neural activity stimulation level is about 0.5 V appliedfor about 0.5 milliseconds.